Summary of your 'study carrel' ============================== This is a summary of your Distant Reader 'study carrel'. The Distant Reader harvested & cached your content into a collection/corpus. It then applied sets of natural language processing and text mining against the collection. The results of this process was reduced to a database file -- a 'study carrel'. The study carrel can then be queried, thus bringing light specific characteristics for your collection. These characteristics can help you summarize the collection as well as enumerate things you might want to investigate more closely. This report is a terse narrative report, and when processing is complete you will be linked to a more complete narrative report. Eric Lease Morgan Number of items in the collection; 'How big is my corpus?' ---------------------------------------------------------- 50 Average length of all items measured in words; "More or less, how big is each item?" ------------------------------------------------------------------------------------ 9089 Average readability score of all items (0 = difficult; 100 = easy) ------------------------------------------------------------------ 47 Top 50 statistically significant keywords; "What is my collection about?" ------------------------------------------------------------------------- 50 rig 30 RNA 27 IFN 8 virus 7 figure 6 MDA5 6 MAVS 5 dna 5 TRIM25 5 PKR 5 IRF3 4 protein 3 sting 3 TLR8 3 TBK1 3 SARS 3 RLR 3 HCV 2 trim 2 ns1 2 TLR7 2 TLR3 2 HIV-1 2 Fig 1 word 1 viral 1 ube1l 1 translation 1 table 1 stat6 1 stat1 1 response 1 replication 1 receptor 1 nucleic 1 ns1/126 1 isg15 1 innate 1 immune 1 gene 1 dub 1 category 1 card 1 USP25 1 UBP43 1 TRAF3 1 TLR9 1 Space 1 Scientific 1 SVV Top 50 lemmatized nouns; "What is discussed?" --------------------------------------------- 4258 virus 3668 protein 3326 rig 3226 cell 2015 response 1895 × 1742 infection 1636 type 1624 activation 1451 receptor 1227 gene 1116 interferon 1097 expression 1084 pathway 1072 domain 1042 host 1017 activity 987 replication 985 i 844 role 781 mechanism 770 factor 754 production 748 interaction 748 function 746 recognition 695 −3 689 study 666 immunity 646 induction 645 dna 601 structure 600 word 593 acid 580 dsrna 575 rna 544 ubiquitin 524 mouse 498 system 495 degradation 476 figure 464 influenza 451 family 437 transcription 436 level 434 complex 430 kinase 420 genome 419 c 411 sensor Top 50 proper nouns; "What are the names of persons or places?" -------------------------------------------------------------- 3033 RNA 2534 IFN 2165 al 1800 . 1757 et 1097 −2 935 I 725 MDA5 611 MAVS 592 C 467 IRF3 460 HCV 402 RNase 401 TRIM25 365 PKR 329 TBK1 294 Fig 280 NF 277 CoV 275 β 272 SARS 266 TLR3 253 L 248 RLR 247 ISG15 245 −3 244 IAV 230 RSV 225 LGP2 219 HIV-1 212 κB 190 RIG- 184 DNA 179 TLR7 176 Toll 170 T 167 TRAF3 165 mRNA 165 TLR 165 IRF7 164 PEDV 161 NS2 156 N 149 B 148 III 147 j 147 TLR8 138 TRIF 126 × 125 A Top 50 personal pronouns nouns; "To whom are things referred?" ------------------------------------------------------------- 2910 i 907 it 639 we 246 they 92 them 34 itself 21 us 15 ns3/4a 14 themselves 13 one 13 he 7 isgf3 6 yubfkt1 5 rig- 5 nsp15 5 me 4 nsp10 4 ifit5 3 you 3 trim21 3 mrnas 2 zbtrim25 2 rnaset2 2 pdcs 2 kap1/ 2 isg15 2 ifih1 1 type- 1 trim13 1 stat6 1 ourselves 1 ours 1 il12p70 1 il-4rα 1 ifit1 1 him 1 cggmaaagacc 1 3cwt Top 50 lemmatized verbs; "What do things do?" --------------------------------------------- 10982 be 1979 have 1700 signal 1527 induce 1104 mediate 1101 bind 1089 activate 940 inhibit 816 show 658 use 602 regulate 538 include 512 associate 502 target 486 infect 479 contain 471 strand 456 suggest 456 require 449 interact 431 involve 400 identify 396 find 390 lead 380 recognize 374 do 355 promote 338 indicate 337 encode 324 express 323 trigger 322 suppress 322 result 318 detect 312 stimulate 301 form 273 demonstrate 271 increase 269 play 267 prevent 261 report 260 block 257 reveal 255 know 246 provide 233 enhance 227 describe 224 sense 221 cause 221 act Top 50 lemmatized adjectives and adverbs; "How are things described?" --------------------------------------------------------------------- 2525 viral 1723 antiviral 1558 immune 1467 innate 1212 also 1162 not 856 - 855 like 720 human 632 other 603 cellular 580 such 550 dependent 546 specific 466 however 421 double 415 different 392 respiratory 346 high 341 several 340 well 339 important 338 essential 329 structural 328 thus 327 more 325 only 320 non 302 many 298 molecular 296 nucleic 267 anti 265 functional 264 cytosolic 260 single 260 most 258 negative 254 regulatory 254 further 250 first 248 then 242 as 241 inducible 230 nuclear 225 positive 219 inflammatory 217 downstream 214 −2 214 multiple 210 early Top 50 lemmatized superlative adjectives; "How are things described to the extreme?" ------------------------------------------------------------------------- 86 most 53 least 21 Most 18 good 17 -I 14 high 9 vRNA 9 large 9 early 7 low 6 strong 5 simple 4 close 2 late 2 great 1 tremeGENE 1 tight 1 small 1 short 1 near 1 long 1 big Top 50 lemmatized superlative adverbs; "How do things do to the extreme?" ------------------------------------------------------------------------ 174 most 28 least 20 well 4 vrna 3 -i 1 highest 1 -o Top 50 Internet domains; "What Webbed places are alluded to in this corpus?" ---------------------------------------------------------------------------- 6 doi.org 2 www.dovepress.com 1 www.ncbi.nlm.nih.gov 1 www.frontiersin.org 1 www.fao.org 1 www.cdc.gov 1 www 1 tree.bio.ed.ac.uk 1 journal.frontiersin.org 1 imagej.net 1 creativecommons.org Top 50 URLs; "What is hyperlinked from this corpus?" ---------------------------------------------------- 1 http://www.ncbi.nlm.nih.gov 1 http://www.frontiersin.org/articles/10.3389/fimmu 1 http://www.fao.org/ag/againfo/programmes/en/empres/h7n9/ 1 http://www.dovepress.com/cancer-management-and-research-journal 1 http://www.dovepress.com/ 1 http://www.cdc.gov/ 1 http://www 1 http://tree.bio.ed.ac.uk/ 1 http://journal.frontiersin.org/article/10.3389/fmicb 1 http://imagej.net/Introduction 1 http://doi.org/10.1371/journal.ppat.1007984.g002 1 http://doi.org/10.1371/journal.ppat.1007984.g001 1 http://doi.org/10.1038/s41401-020-0403-9 1 http://doi.org/10.1016/j.semcdb.2020.08.006 1 http://doi.org/10.1016/j.bbrc.2020.04.060 1 http://doi.org/10.1016/j.antiviral.2018.10.028 1 http://creativecommons.org/licenses/by-nc-nd/3.0/ Top 50 email addresses; "Who are you gonna call?" ------------------------------------------------- Top 50 positive assertions; "What sentences are in the shape of noun-verb-noun?" ------------------------------------------------------------------------------- 12 genes encoding c 10 ifn signaling pathway 10 interferon signaling pathway 9 ifn signaling pathways 7 cell signaling pathways 7 receptor signaling pathway 6 cells were mock 6 i signaling cascades 6 interferon signal transduction 6 protein binds double 6 protein inhibits type 6 rna requires base 5 factor promoting rig 5 protein induces template 5 protein signaling cascades 5 receptor recognizes bacterial 5 replication is not 5 virus infected cells 4 cells were co 4 factor regulates nuclear 4 ifn signal transduction 4 protein is also 4 proteins are also 4 proteins regulate autophagy 4 rna binding proteins 4 viruses encode proteins 4 viruses have also 3 activity is independent 3 activity is not 3 cells are more 3 cells did not 3 cells does not 3 cells were then 3 expression is up 3 expression was significantly 3 factor signaling pathways 3 genes encoding rig 3 genes encoding toll 3 host encoded rbps 3 ifn signaling cascade 3 interferon signaling independent 3 protein does not 3 protein inhibits activation 3 protein inhibits host 3 protein is critical 3 proteins regulate hcv 3 proteins were then 3 receptor signaling pathways 3 receptors activate mavs 3 responses involving regulation Top 50 negative assertions; "What sentences are in the shape of noun-verb-no|not-noun?" --------------------------------------------------------------------------------------- 1 activation is not yet 1 activity is not intrinsic 1 activity is not necessary 1 cell does not really 1 cells are not permissive 1 cells are not very 1 cells did not significantly 1 cells do not normally 1 cells were no longer 1 cells were not apparently 1 domain is not capable 1 domains is not yet 1 gene is not there 1 genes are not present 1 infection had no impact 1 infection is not completely 1 infection is not entirely 1 infection were not entirely 1 pathway are not well 1 pathway is not present 1 pathway is not well 1 protein does not necessarily 1 replication has not yet 1 replication is not fully 1 response are not well 1 response was not limited 1 rna have not yet 1 rna is not sequence 1 rna is not sufficient 1 rna was not able 1 virus do not efficiently 1 viruses are not likewise 1 viruses do not self 1 viruses is not entirely 1 viruses was not due A rudimentary bibliography -------------------------- id = cord-257052-cik2wmlk author = Ban, Junsu title = Human Respiratory Syncytial Virus NS 1 Targets TRIM25 to Suppress RIG-I Ubiquitination and Subsequent RIG-I-Mediated Antiviral Signaling date = 2018-12-14 keywords = TRIM25; ns1; rig summary = title: Human Respiratory Syncytial Virus NS 1 Targets TRIM25 to Suppress RIG-I Ubiquitination and Subsequent RIG-I-Mediated Antiviral Signaling Collectively, this study suggests that RSV NS1 interacts with TRIM25 and interferes with RIG-I ubiquitination to suppress type-I interferon signaling. Ectopically expressed NS1 inhibited interferon-β promoter activity that was induced by RIG-IN as determined by the luciferase assays in HEK293T cells, confirming that NS1 itself is capable of inhibiting RIG-I-mediated antiviral signaling ( Figure 1A ). Ectopically expressed NS1 inhibited interferon-β promoter activity that was induced by RIG-IN as determined by the luciferase assays in HEK293T cells, confirming that NS1 itself is capable of inhibiting RIG-I-mediated antiviral signaling ( Figure 1A ). These results suggest that RSV NS1 expression diminishes the interaction between RIG-I and MAVS by interfering with TRIM25-mediated RIG-I ubiquitination. These results indicate that inhibition of TRIM25-mediated RIG-I ubiquitination by NS1 contributes to the suppression of RIG-I signaling, at least in part. doi = 10.3390/v10120716 id = cord-307914-lgprrwee author = Bartok, Eva title = Immune Sensing Mechanisms that Discriminate Self from Altered Self and Foreign Nucleic Acids date = 2020-07-14 keywords = IFN; RNA; TLR3; TLR7; TLR8; dna; rig; sting summary = Indeed, the functionalization of CRISPR/Cas systems as a tool for genomic editing have revealed important differences in human and murine NA sensing, including distinct cell subset expression patterns of NA-sensing Toll-Like Receptors (TLRs) or species differences in the structural requirements for the detection of cyclic dinucleotide cGAMP by STING. As a long dsRNA with a 5 0 diphosphate terminus, polyI:C is known to activate the sensing receptors TLR3, MDA5, and RIG-I (Alexopoulou et al., 2001; Gitlin et al., 2006; Kato et al., 2008; Yoneyama et al., 2005) , accessory proteins such including LGP2 and members of the DDX and DHX families (reviewed in Oshiumi et al., 2016) as well as the restriction factors PKR and the OAS family (Farrell et al., 1978; Hovanessian et al., 1977; Zilberstein et al., 1978) . doi = 10.1016/j.immuni.2020.06.014 id = cord-002689-qakbp4dz author = Brisse, Morgan title = Viral inhibitions of PACT-induced RIG-I activation date = 2017-07-03 keywords = rig summary = Influenza virus NS1, MERS-CoV 4a, herpesvirus HSV1 Us11, and ebola virus VP35 proteins have all been shown to directly disrupt the interaction between RIG-I and PACT, and hence blocks the ability of PACT to activate RIG-I (4-7). All these viral proteins have RNA binding capabilities, yet it isn''t clear from the published reports whether dsRNA is absolutely required to activate RIG-I via PACT induction. When HEK293T cells were transfected with 4a from dsRNA binding MERS-CoV and bCoV-HKU5 and non-dsRNA binding bCoV-HKU4, the IFNβ promoter activity was suppressed in the dsRNA binding 4a expressing cells but was not affected in the non-dsRNA 4a expressing cells, indicating that dsRNA binding is necessary for inhibition of IFN1 production [5] . Like influenza NS1 and MERS-CoV 4a proteins, Us11 protein of HSV1 is a dsRNA binding protein and has been shown to associate with PACT, PKR, MDA5 and RIG-I in addition to 2′,5′-oligoadenylate synthetase (OAS). These known viral proteins have RNA-binding properties, yet it still isn''t entirely clear whether RNA binding is an absolute requirement to inhibit PACT-induced RIG-I activation. doi = 10.18632/oncotarget.18928 id = cord-350836-1enteev7 author = Brisse, Morgan title = Comparative Structure and Function Analysis of the RIG-I-Like Receptors: RIG-I and MDA5 date = 2019-07-17 keywords = IFN1; MAVS; MDA5; RNA; TRIM25; card; figure; rig summary = RIG-I (Retinoic acid-inducible gene I) and MDA5 (Melanoma Differentiation-Associated protein 5), collectively known as the RIG-I-like receptors (RLRs), are key protein sensors of the pathogen-associated molecular patterns (PAMPs) in the form of viral double-stranded RNA (dsRNA) motifs to induce expression of type 1 interferons (IFN1) (IFNα and IFNβ) and other pro-inflammatory cytokines during the early stage of viral infection. For the former, siRNA-mediated knock-down (110, 111) , cellular knockout (112) and inhibition by viral protein (109, (113) (114) (115) (116) conditions for TRIM25 in multiple cell types have been shown to change RIG-I cellular localization (110) and to negatively affect RIG-I K63 ubiquitination, association with MAVS and IFN signaling [when the constitutively active RIG-I CARD domain was overexpressed (109, (112) (113) (114) (115) (116) or during viral infection (109, 111, 114) ]. doi = 10.3389/fimmu.2019.01586 id = cord-261532-q923xxn2 author = Chen, Huihui title = The essential adaptors of innate immune signaling date = 2012-09-21 keywords = IL-4; MAVS; RNA; rig; stat6; sting summary = Microbial components and the endogenous molecules released from damaged cells can stimulate germ-line-encoded pattern recognition receptors (PRRs) to transduce signals to the hub of the innate immune signaling network-the adaptor proteins MyD88/TRIF/MAVS/STING/Caspase-1, where integrated signals relay to the relevant transcription factors IRF3/IRF7/NF-κB/ AP-1 and the signal transducer and activator of transcription 6 (STAT6) to trigger the expression of type I interferons and inflammatory cytokines or the assembly of inflammasomes. These receptors can recruit specific adaptor proteins, like myeloid differentiation primary response gene 88 (MyD88) or Toll/interleukin-1 receptor (TIR) domain-containing adaptor inducing IFN-β (TRIF) in the TLR pathway, mitochondrial antiviral signaling protein (MAVS) downstream of RLRs, stimulator of interferon genes (STING) in the cytosolic DNA response pathway and, cysteine aspartic protease 1 (Caspase-1) as part of the inflammasome, all of which orchestrate the host innate responses, through activation of transcriptional factors such as nuclear factor κB (NF-κB), activator protein 1 (AP-1) and interferon regulatory factors (IRFs), to trigger the production of type І interferons (IFNs), inflammatory cytokines and chemokines. doi = 10.1007/s13238-012-2063-0 id = cord-312892-p72zwmtb author = Chen, Nanhua title = RNA sensors of the innate immune system and their detection of pathogens date = 2017-04-04 keywords = RNA; TLR7; TLR8; rig summary = It in turn causes the multimerization of cytoplasmic TIR domains, which will recruit downstream adaptors TRIF or MyD88 through homotypic interaction, further forming signaling complex called signalosome and activating downstream transcription factors: one is NF-jB that induces proinflammtory cytokines, another is interferon regulatory factor (IRF) that induces anti-viral type I Interferon (IFN) (6) . The summary of cellular localizations and distributions, ligand recognitions, activation mechanisms, cell signaling, recognition of pathogens, and cross-talks for RNA PRRs (2) TLR3 (2) RIG-I (2) The understanding of RNA PRR immune biology including the ligand recognitions, cellular localizations, cell signaling pathways, mechanisms of activation, recognized pathogens and the interactions between different RNA PRRs will definitely be helpful to improve the anti-viral immune response. Third, TLR3, 7, 8 are primarily expressed by macrophages and DCs and recognize viral RNA within the endosomal compartment, whereas RLRs (RIG-I, MDA5) and NLRs (NLRP3, NOD2) are ubiquitously expressed and sense viral RNA within the cytoplasm of infected cells (Table 1 ). doi = 10.1002/iub.1625 id = cord-303189-ktl4jw8v author = Coccia, Eliana M. title = Early IFN type I response: Learning from microbial evasion strategies date = 2015-03-31 keywords = HCV; HIV-1; IFN; IRF3; PKR; RNA; rig; stat1 summary = Acting in both autocrine and paracrine manner, IFN interferes with viral replication by inducing hundreds of different IFN-stimulated genes with both direct anti-pathogenic as well as immunomodulatory activities, therefore functioning as a bridge between innate and adaptive immunity. In these cells, the HCV-induced miR-21 has been recently reported to be involved in evasion of IFN-I production and stimulation of HCV replication, upon suppression of MyD88 and IRAK1 expression, that is required for the TLR7-mediated sensing of the virus [100] . Amongst RNA viruses that, as HCV, can establish a persistent infection, HIV-1, a lentivirus from the Retroviridae family, represents a paradigm for its ability to prevent or circumvent the innate immune response mediated by IFN-I. Overall, viruses as HCV and HIV-1 have evolved nifty strategies to dampen the host innate response in cells where a productive infection may take place, while they induce infection-independent mechanisms in non-permissive cells to facilitate the viral life cycle and promote a chronic inflammation. doi = 10.1016/j.smim.2015.03.005 id = cord-301362-f3lp10lm author = Delgui, Laura R. title = A Novel Mechanism Underlying the Innate Immune Response Induction upon Viral-Dependent Replication of Host Cell mRNA: A Mistake of +sRNA Viruses'' Replicases date = 2017-01-20 keywords = RNA; replication; rig; virus summary = Recognition of viral double-strand RNA (dsRNA) molecules by intracellular Toll-like receptors (TLRs) or retinoic acid inducible gene I-like receptors (RLRs) is a central event which entails the early steps of the immune response elicited during viral infections. Despite several differences among host range, viral structure, genome organization or membrane-donor organelles from the cell, these analyses revealed that +sRNA viruses are able to induce two types of membranous modifications as replicative niches: invaginated vesicles or spherules or a double membrane vesicle type. Endogenous RNAs forming secondary double-stranded structures that are released after necrosis and tissue damage after viral infection represent another source of dsRNA molecules reaching the endosomes, inducing host-derived dsRNA-mediated inflammatory responses through TLR-3 recognition (Kawai and Akira, 2010) . Other +sRNA viruses such as the enterovirus Coxsackievirus (Kemball et al., 2010) , Hepatitis C virus (Flaviviridae family) (Sir et al., 2012) , or Coronavirus such as MVH (Reggiori et al., 2010) also usurp the autophagy pathway and induce remarkably alterations in intracellular membranous components to harbor the sites for viral RNA replication. doi = 10.3389/fcimb.2017.00005 id = cord-254895-ym0jsir5 author = Eisenächer, Katharina title = The role of viral nucleic acid recognition in dendritic cells for innate and adaptive antiviral immunity date = 2008-01-18 keywords = IFN; RNA; TLR3; rig summary = Dendritic cell subpopulations express specific nucleic acid recognition receptors belonging to the Toll-like receptor family (TLR3, 7, 8, 9) and the cytosolic RNA helicase family (RIG-I, MDA5, LGP2). Apart from activating the NFkB and MAPK signaling pathways leading to inflammatory cytokine and chemokine production as well as costimulatory molecule expression, the intracellularly localized nucleic acid recognition receptors TLR3, 7, 8 and 9 specifically trigger type I interferon production via MyD88-and TRIF-dependent signaling pathways. Thus, TRAF6 seems to be required for NFkB activation but not IFN-b induction downstream of IPS-1 which is mainly mediated by TBK1/IKKe. In vitro studies performed with primary cells obtained from RIG-I knockout mice confirmed that RIG-I plays an essential role in eliciting immune responses against specific negative strand and positive strand RNA viruses such as NDV, SeV, VSV, Japanese encephalitis virus (JEV) and Influenza virus in various cell types with the exception of pDCs . doi = 10.1016/j.imbio.2007.09.007 id = cord-321607-3r736dnk author = Ezelle, Heather J. title = The Roles of RNase-L in Antimicrobial Immunity and the Cytoskeleton-Associated Innate Response date = 2016-01-08 keywords = FLNA; LNX; RNA; RNase; rig summary = The active nuclease then cleaves ssRNAs, both cellular and viral, leading to downregulation of their expression and the generation of small RNAs capable of activating retinoic acid-inducible gene-I (RIG-I)-like receptors or the nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome. Although cleavage of RNA virus genomes appeared as the most direct mechanism of action, other important pathways have become evident, such as the regulation of host gene expression, stimulation of IFNβ production, activation of the NACHT, LRR, and PYD-containing protein-3 (NLRP3) inflammasome, and maintenance of the cell''s structural barrier to infection [27, 55, 83, 84] . These small RNAs are capable of stimulating RIG-I and MDA5 (melanoma differentiation associated gene-5) to activate mitochondrial antiviral signaling protein (MAVS) and induce the subsequent translocation of interferon regulatory factor 3 (IRF3) to the nucleus to drive transcription of IFNβ. doi = 10.3390/ijms17010074 id = cord-287855-jfrg9soy author = Gaur, Pratibha title = Influenza virus and cell signaling pathways date = 2011-06-01 keywords = MAPK; rig summary = During viral infection there is activation of the NF-kB signaling pathway and an increase in the gene expression levels of IFN-b/TNFa/IL8 [22, 23] , which suggests that IKK-mediated NF-kB signaling is essential for the host innate immune response [24] . Activation of Akt through phosphorylation at Thr 308 and Ser 473 residues [42] plays a major role in modulating diverse downstream signaling pathways, including cell survival, proliferation, migration, differentiation and inhibition of proapoptotic factors such as BAD and caspase-9 by their phosphorylation (Figure 1(1) ). Mitogen activated protein kinase (MAPK) cascades are involved in the conversion of various extracellular signals into cellular responses as diverse as proliferation, differentiation, immune response and cell death [51, 52] . Binding of influenza virus HA protein to host cell surface receptor activates PKC [12, 77, 78] , and overexpression of HA inside the cells induces ERK signaling. Most importantly, NS1 protein reduces the antiviral response by activating NF-kB signaling and also activates PI3K/Akt pathway for efficient viral replication. doi = 10.12659/msm.881801 id = cord-346916-jj4l9ydl author = Girardi, Erika title = Roadblocks and fast tracks: How RNA binding proteins affect the viral RNA journey in the cell date = 2020-08-23 keywords = Fig; PKR; RNA; protein; rig; translation; viral; virus summary = Moreover, despite the molecular mimicry set by RNA viruses to resemble cellular mRNAs and escape host recognition, the viral nucleic acid still needs to embark on a long journey through a hostile cell environment and must overcome the obstacles put in place by the host antiviral system in order to be translated and replicated. Another example, is the zinc-finger antiviral protein (ZAP), which binds vRNAs containing a ZAP response element (ZRE) and induces RNA degradation via interaction of its N-terminal domain with host decay machinery mediated [75] (Fig. 1 ). In fact, IRES elements present in the genome of different families of RNA viruses lack overall conserved features [146, 147] .The classification of viral IRESs in four types stems from their structural organization, their respective dependence on sets of translation initiation factors, and whether they use scanning or instead directly recruit ribosomes to the start codon [148] (Fig. 2) . doi = 10.1016/j.semcdb.2020.08.006 id = cord-288390-p1q3v1ie author = Habjan, Matthias title = Cytoplasmic sensing of viral nucleic acids date = 2015-02-07 keywords = MDA5; RNA; dna; rig summary = These sensors induce expression of cytokines, affect cellular functions required for virus replication and directly target viral nucleic acids through degradation or sequestration. These sensors induce expression of cytokines, affect cellular functions required for virus replication and directly target viral nucleic acids through degradation or sequestration. In this review we concentrate on intracellular nucleic acid sensors and effector proteins that evolved to mediate specialised tasks including, firstly, expression of cytokines such as type I interferons (IFN-a/b); secondly, modulation of cellular machineries required for virus replication and thirdly, direct inhibition of virus growth ( Figure 1 ). Among the best characterised cytoplasmic proteins involved in virus sensing are RIG-I-like receptors (RLRs), a family of DExD/H-box helicases which specifically identify viral RNAs and have the ability to stimulate expression of IFN-a/b and other cytokines (Figure 3 ) [4, 17] . Virus infection activates a restricted set of sensor and effector proteins that modulate cellular pathways and directly target viral nucleic acid, thereby shaping the innate immune response. doi = 10.1016/j.coviro.2015.01.012 id = cord-007382-5kb16qb7 author = Hartmann, G. title = Nucleic Acid Immunity date = 2016-12-15 keywords = IFN; PKR; RNA; SAMHD1; TLR9; dna; nucleic; rig summary = With the additions of RNAi and the CRISPR/Cas system, specific nucleases including the restriction-modification (R-M) systems, and antiviral effector proteins partially discovered only recently in the context of rare hereditary inflammatory diseases, the new concept of nucleic acid immunity evolves. While innate nucleic acid immune-sensing receptors elicit antiviral signaling pathways, a number of nucleic acid-detecting effector proteins (viral restriction factors, e.g., PKR, ADAR1, IFIT1) directly detect and restrict nucleic acid function and replication. Another member of the RIG-I-like helicase family of receptors is MDA5 which was found to be responsible for the long sought after type I IFN-inducing activity of cytosolic long double-stranded RNA including poly(I:C) . Extrinsic effects inside the same cell include degradation of the nucleic acid (e.g., RNase L activated by 2 0 -5 0 -OA generated by OAS1 upon binding of long double-stranded RNA). doi = 10.1016/bs.ai.2016.11.001 id = cord-254492-42d77vxf author = Heaton, Steven M. title = Ubiquitin in the activation and attenuation of innate antiviral immunity date = 2016-01-11 keywords = IFN; IRF3; MAVS; RLR; rig summary = Here we review how hostand virus-directed ubiquitin modification of proteins in the RLR, NLR, and TLR antiviral signaling cascades modulate IFN-I expression. Methods for this include substrate molecular mimicry, binding and blocking E3-substrate pairs, expressing virally encoded E3s/DUbs, and hijacking host E3s/DUbs. Additionally, a novel mechanism involving ubiquitin chain packaging into nascent virions for subsequent redeployment Viral infection activates danger signals that are transmitted via the retinoic acid-inducible gene 1-like receptor (RLR), nucleotide-binding oligomerization domain-like receptor (NLR), and Toll-like receptor (TLR) protein signaling cascades. Here we review how host-and virus-directed ubiquitin modification of proteins in the RLR, NLR, and TLR antiviral signaling cascades modulate IFN-I expression. RNF125 forms part of this process, ligating K48-linked polyubiquitin chains to the activated CARD of RIG-I and MDA5, leading to proteasome-mediated degradation of both receptors and diminished IFN-I signaling. MAVS ubiquitination by the E3 ligase TRIM25 and degradation by the proteasome is involved in type I interferon production after activation of the antiviral RIG-I-like receptors doi = 10.1084/jem.20151531 id = cord-283096-qm7h4qui author = Jeon, Young Joo title = ISG15 and immune diseases date = 2010-02-12 keywords = IFN; ISG15; UBP43; protein; rig; ube1l summary = Some of them are type I IFN-induced proteins, such as PKR and RIG-I, and some are the key regulators that are involved in IFN signaling, such as JAK1 and STAT1, implicating the role of ISG15 and its conjugates in type I IFN-mediated innate immune responses. Viral infection also strongly induces ISG15 [18, 19] because one of its major host responses is the production of type I IFNs. A number of proteins that are involved in antiviral signaling pathways, including RIG-I, MDA-5, Mx1, PKR, STAT1, and JAK1, have been identified as target proteins for ISGylation. Swiss 3T3 cells expressing constitutively active MKK7-JNK1β fusion protein show increased resistance to apoptosis induced by vesicular stomatitis virus (VSV) infection, suggesting the involvement of JNK signaling pathway in antiviral response. acid seems to elevate the levels of ISG15 and its conjugates by stimulating cells to secrete IFNs. UBE1L is a 112-kDa protein that shows a 45% identity in amino acid sequence to the human ubiquitin-activating E1 enzyme (UBE1) [73] . doi = 10.1016/j.bbadis.2010.02.006 id = cord-268438-bjs5oliw author = Jin, Yilin title = Zebrafish TRIM25 Promotes Innate Immune Response to RGNNV Infection by Targeting 2CARD and RD Regions of RIG-I for K63-Linked Ubiquitination date = 2019-12-03 keywords = IFN; RLR; rig summary = title: Zebrafish TRIM25 Promotes Innate Immune Response to RGNNV Infection by Targeting 2CARD and RD Regions of RIG-I for K63-Linked Ubiquitination Here, we found that zebrafish TRIM25 (zbTRIM25) functioned as a positive regulator of RLR signaling pathway during red spotted grouper nervous necrosis virus (RGNNV) infection. In the present study, zebrafish TRIM25 (zbTRIM25) was involved in RGNNV infection and was identified as a positive mediator of RLR signaling pathway by binding to and ubiquitinating the caspase activation and recruitment domain (2CARD) and repressor domain (RD) regions of RIG-I, which is different with the findings in mammals. In mammals, previous reports showed that TRIM25 enhanced RLRs antiviral pathway by binding viral RNA-activated RIG-I to induce its K63-linked polyubiquitination and subsequent IFNs and ISGs production (26) . Here, we found that zbTRIM25 positively regulated RLR signaling pathway and facilitated zbRIG-I-mediated IFN 1 promoter activation, and overexpression of zbTRIM25 inhibited RGNNV infection, indicating the conservative antiviral properties of TRIM25 in fish and mammals. doi = 10.3389/fimmu.2019.02805 id = cord-311823-85wj08gr author = Katze, Michael G. title = Innate immune modulation by RNA viruses: emerging insights from functional genomics date = 2008 keywords = HCV; IFN; response; rig; virus summary = In this section, we review recent studies in which genomic approaches have been used to provide new information on how viruses trigger and regulate innate immune pathways, and to evaluate the use of type I IFN-based therapy as a means to enhance the innate immune response to HCV. In RIg-I-deficient cells, influenza virus fails to elicit the expression of IFNβ and of many ISgs, including key antiviral mediators such as IRF3, STAT1 (signal transducer and activator of transcription 1), IFIT1 (IFN-induced protein with tetratricopeptide repeats 1; also known as ISg56) and ISg54 (also known as IFIT2). Although these studies have provided considerable information regarding the genes activated downstream of TlR activation, it will be advantageous to extend genomic analyses in the context of viral infection using cells lacking the expression of specific TlRs. The ability of a virus to establish an infection depends, at least to some extent, on its ability to block the host innate immune response or to modulate the activity of antiviral effector proteins. doi = 10.1038/nri2377 id = cord-000125-uvf5qzfd author = Kenworthy, Rachael title = Short-hairpin RNAs delivered by lentiviral vector transduction trigger RIG-I-mediated IFN activation date = 2009-09-03 keywords = B971; IFN; RNA; figure; rig summary = The interaction between a PAMP and a PRR triggers activation of the interferon (IFN) pathway in mammalian cells, which significantly changes the gene-expression profile in the cells and contributes to the well-documented off-target effect of RNAi. IFN induction is especially problematic in antiviral studies employing RNAi, where the antiviral effect of IFN must be distinguished from that of RNAi. Typical IFN-inducing structure patterns include dsRNA of certain length, single-stranded RNA (ssRNA) containing 5 0 -triphosphates (5 0 -ppp), the dsRNA analogue polyinosinic-polycytidylic acid (poly I:C), and certain dsDNA molecules. Mammalian expression plasmids encoding each of these proteins, as well as the dominant negative (DN) mutants of RIG-I and MDA5, were transfected into 293FT cells with shRNAs and an IFN-b promoter reporter construct. doi = 10.1093/nar/gkp714 id = cord-328252-dk54w8z9 author = Kikkert, Marjolein title = Innate Immune Evasion by Human Respiratory RNA Viruses date = 2019-10-14 keywords = IFN; RNA; immune; innate; rig; virus summary = Whether PA-X also degrades viral dsRNA species to prevent recognition by cytosolic RNA sensors is not entirely clear, but mutant viruses in which this PA-X protein was expressed in significantly lower amounts elicited higher levels of innate immune response; for example, IFN-beta production was much higher in these infections [71] . This indeed suggests that PA-X, besides having a role in the degradation of cellular mRNAs, may also degrade viral RNA to prevent recognition by innate immune sensors and activation of innate immune responses, similar to what was shown for the CoVs. To my knowledge, an endoribonuclease has not been identified in the RSV genome, so this virus may use alternative innate immune evasion strategies, as discussed elsewhere in this review. [91] suggested that RSV specifically targets mRNA encoding surfactant protein A, an innate immune factor with an important role in the epithelial tissue of the lung, which directly binds to virus particles to cause their destruction by host defense mechanisms. doi = 10.1159/000503030 id = cord-254549-ev0oesu0 author = Kutikhin, Anton G title = C-type lectin receptors and RIG-I-like receptors: new points on the oncogenomics map date = 2012-02-24 keywords = receptor; rig summary = The fundamental basis for the association of the inherited coding variation in genes encoding C-type lectin receptors and RIG-I-like receptors with cancer is represented by the defects in the immune response (that are caused by various single nucleotide polymorphisms) against specific carcinogenic infectious agents. The issue of an association of single nucleotide polymorphisms of genes encoding C-type lectin receptors, RIG-I-like receptors, and proteins of pattern recognition receptor pathways with various features of cancer progression is open, and only further population studies would be likely to give a definite answer. Another interesting issue is that associations between single nucleotide polymorphisms of genes encoding C-type lectin receptors and RIG-I-like receptors and cancer risk can be skewed by differences between cohorts in various immune responses and infections that may not influence cancer development. doi = 10.2147/cmar.s28983 id = cord-001129-gi2kswai author = Lemos de Matos, Ana title = Positive Evolutionary Selection On the RIG-I-Like Receptor Genes in Mammals date = 2013-11-27 keywords = LGP2; MDA5; figure; rig summary = Because viruses are responsible for a great number of severe and lethal diseases, together with the important role that RLRs play in mammalian innate immune system, we expect that RIG-I, MDA5 and LGP2 genes may have been under intense selective pressures in all mammals. Evidence for positive selection on mammalian orthologous for RIG-I ( Figure S7 ), MDA5 ( Figure S8 ) and LGP2 ( Figure S9 ) genes was detected using PAML package [54, 55] site-specific models M1a versus M2a and M7 versus M8. (C) Positively-selected codons are exhibited in the table and numbered according to the mammalian LGP2 deduced protein sequences alignment ( Figure S6 downstream RIG-I and MDA5 signaling, which implies functional constraints, the observed variability across species can be perceived as a great structural plasticity for mammalian CARDs. The helicase domain in the RLR family is generally described as exhibiting affinity for dsRNA [78] . doi = 10.1371/journal.pone.0081864 id = cord-327000-oyg3oyx1 author = Li, Shasha title = Porcine Epidemic Diarrhea Virus and the Host Innate Immune Response date = 2020-05-11 keywords = IFN; PEDV; RNA; SARS; protein; rig; virus summary = This review highlights the immune evasion mechanisms employed by PEDV, which provides insights for the better understanding of PEDV-host interactions and developing effective vaccines and antivirals against CoVs. Porcine epidemic diarrhea virus (PEDV) is the etiological agent of porcine epidemic diarrhea (PED) that causes an acute and highly contagious enteric disease of swine characterized by vomiting, diarrhea, dehydration, and anorexia in pigs of all ages, especially resulting in severe diarrhea and high mortality rate in piglets. Nsp3 is the largest nsp protein, containing two papain-like protease (PLP1 and PLP2) domains, of which PEDV PLP2 acts as a viral deubiquitinase (DUB), to negatively regulate type I IFN signaling [80] . The evasive strategies utilized by PEDV are classified into four major types: (1) inhibition of RLRs-mediated IFN production pathways, (2) inhibition of the activation of transcription factors responsible for IFN induction, (3) disruption of the signal cascades induced by IFN, and (4) hiding its viral RNA to avoid the exposure of viral RNA to immune sensors. doi = 10.3390/pathogens9050367 id = cord-284156-btb4oodz author = Liu, Yiliu title = Host and Viral Modulation of RIG-I-Mediated Antiviral Immunity date = 2017-01-03 keywords = MAVS; RNA; TRIM25; rig; virus summary = Retinoic acid-inducible gene-I (RIG-I) is critical in triggering antiviral and inflammatory responses for the control of viral replication in response to cytoplasmic virus-specific RNA structures. They function as cytoplasmic sensors for the recognition of a variety of RNA viruses and subsequent activation of downstream signaling to drive type I IFN production and antiviral gene expressions. (c) Interactions between RIG-I-TRIM25 complex and 14-3-3ϵ promote RIG-I translocation to mitochondrial mitochondrial antiviral signaling protein (MAVS) for downstream signaling, leading to interferon production. Protein purification and mass spectrometry analysis identified that phosphorylation of Thr170 in the CARDs antagonizes RIG-I signaling by inhibiting TRIM25-mediated Lys172 ubiquitination and MAVS binding (68) . Ebola virus VP35 protein binds double-stranded RNA and inhibits alpha/beta interferon production induced by RIG-I signaling Inhibition of dengue and chikungunya virus infections by RIG-I-mediated type I interferon-independent stimulation of the innate antiviral response doi = 10.3389/fimmu.2016.00662 id = cord-313138-y485ev30 author = Magor, Katharine E. title = Defense genes missing from the flight division date = 2013-04-24 keywords = MHC; RNA; TLR8; gene; rig summary = Whether cause or effect, the lack of TLR8 in avian monocytes/ macrophages likely does contribute to the susceptibility of birds to RNA viruses (West Nile virus, Newcastle disease virus, influenza virus and others) and intracellular bacterial infections, including mycobacteria. The gene encoding RIG-I, DDX58, is not annotated in the chicken genome sequence, and is missing in some fish species, but MDA5 homologues are present in all vertebrate families (Zou et 2009). Riplet/RNF135 is a cytoplasmic E3-ligase identified by yeast two-hybrid as one of the proteins binding RIG-I, and is essential for RIG-I activation in human cell lines upon infection with an RNA virus (Oshiumi et al., 2009; Oshiumi et al., 2010) . The upregulation of IFIT5 following viral infection of chicken cells expressing duck RIG-I ( Barber et al., 2013) or infection of ducks (Vanderven et al., 2012) suggests IFIT5 is an important antiviral effector in avian species. doi = 10.1016/j.dci.2013.04.010 id = cord-312001-8p7scli8 author = Majzoub, Karim title = The Innate Antiviral Response in Animals: An Evolutionary Perspective from Flagellates to Humans date = 2019-08-16 keywords = IFN; MAVS; MDA5; RNA; dna; rig; sting summary = Consequently, animal cells have evolved devoted pathways which (1) sense and recognize pathogen-associated molecular patterns (PAMPs) and, more particularly, virus-associated molecular signatures; (2) initiate signaling cascades stemming from the site of detection, translocating the information to the nucleus; and (3) induce a transcriptional program that confers an antiviral state to the host ( Figure 1 ). While the cytosolic recognition of viral RNA is almost exclusively mediated by RLRs, several proteins have been proposed to play a role in DNA sensing and triggering innate immune responses, such as the DNA-dependent activator of IFN-regulatory factors (DAI), DDX41, RNA polymerase III, IFI16 and DNA-PK [62] [63] [64] [65] [66] [67] . Although the pathway leading to the transcriptional activation of Vago is still poorly understood in insects, these studies established that DExD/H-box helicase containing proteins, like Dicer and RLRs, may represent an evolutionarily conserved set of viral nucleic acid sensors that direct antiviral responses in animals [159] . doi = 10.3390/v11080758 id = cord-313957-hviv5zar author = Masucci, Maria Grazia title = Viral Ubiquitin and Ubiquitin-Like Deconjugases—Swiss Army Knives for Infection date = 2020-08-01 keywords = BPLF1; IFN; SARS; dna; isg15; rig summary = UbL-specific proteases can reverse the modification, supplementing the cellular pools of free UbLs. The attachment of a Ub moiety to the N-terminal Met1 or to an internal Lys residue of the previous Ub (K6, K11, k27,K29,K33,K48 or K63) results in the formation of topologically different poly-Ub chains that, upon recognition by signal transducers contain dedicated binding domains, target the substrates various fates and cellular functions Ubiquitin is the first recognized and best-known member of the family. UbL-specific proteases can reverse the modification, supplementing the cellular pools of free UbLs. The attachment of a Ub moiety to the N-terminal Met1 or to an internal Lys residue of the previous Ub (K6, K11, k27,K29,K33,K48 or K63) results in the formation of topologically different poly-Ub chains that, upon recognition by signal transducers contain dedicated binding domains, target the substrates various fates and cellular functions Ubiquitin is the first recognized and best-known member of the family. doi = 10.3390/biom10081137 id = cord-328549-r56lih8j author = Okamoto, Masaaki title = Regulation of RIG-I Activation by K63-Linked Polyubiquitination date = 2018-01-05 keywords = Riplet; rig summary = First, it was reported that TRIM25 ubiquitin ligase delivered K63-linked polyubiquitin moiety to the 2CARDs. The polyubiquitin chain stabilizes a structure called the 2CARD tetramer, in which four 2CARDs assemble and make a core that promotes the aggregation of the mitochondrial antiviral-signaling (MAVS) protein on mitochondria. First, it was reported that TRIM25 ubiquitin ligase delivered K63-linked polyubiquitin moiety to the 2CARDs. The polyubiquitin chain stabilizes a structure called the 2CARD tetramer, in which four 2CARDs assemble and make a core that promotes the aggregation of the mitochondrial antiviral-signaling (MAVS) protein on mitochondria. However, subsequent studies have reported that Riplet, MEX3C, and TRIM4 ubiquitin ligases are also involved in K63-linked polyubiquitination and the activation of RIG-I. However, recent studies have reported three other ubiquitin ligases, RING finger protein leading to RIG-I activation (Riplet), mex-3 RNA-binding family member C (MEX3C), and TRIM4, which are required for the polyubiquitination and activation of RIG-I (28-30). doi = 10.3389/fimmu.2017.01942 id = cord-312886-o3ipzn05 author = Onomoto, Koji title = Antiviral innate immunity and stress granule responses date = 2014-08-19 keywords = PKR; RNA; rig summary = Viral infection and stress granules Viral invasion and replication are detected by innate immune sensors in cells, triggering downstream signaling pathways that can ultimately result in the activation of systemic immune responses. In some cases these bodies have been given different names in an attempt to distinguish them from SGs; in this review, however, we refer to virusinduced SG-like granules collectively as SGs. Many viruses induce SGs through the activation of the eukaryotic translation initiation factor (eIF)2a kinases PKR and, in some cases, general control non-depressible 2 (GCN2), which are both triggered by detection of RNA in the cytoplasm [28] ( Figure 2 ). In the stress-recovered condition, GADD34 protein is rapidly downregulated by an unknown mechanism and the phosphorylated form of eIF2a reaccumulates in the cells, resulting in an oscillating pattern of SGs. In cases where viral infection appears to not induce SGs, accumulating evidence suggest that these viruses inhibit SG formation. doi = 10.1016/j.it.2014.07.006 id = cord-343824-00mqmpzw author = Qian, Wei title = The C-Terminal Effector Domain of Non-Structural Protein 1 of Influenza A Virus Blocks IFN-β Production by Targeting TNF Receptor-Associated Factor 3 date = 2017-07-03 keywords = IFN; TRAF3; ns1/126; rig summary = title: The C-Terminal Effector Domain of Non-Structural Protein 1 of Influenza A Virus Blocks IFN-β Production by Targeting TNF Receptor-Associated Factor 3 Influenza A virus non-structural protein 1 (NS1) antagonizes interferon response through diverse strategies, particularly by inhibiting the activation of interferon regulatory factor 3 (IRF3) and IFN-β transcription. Hence, binding of the NS1 protein to dsRNA, RIG-I, and TRIM25 has not established that these NS1 interactions are responsible for inhibiting the activation of IRF3 and IFN transcription. These data reveal a novel mechanism for how the influenza A virus NS1 protein induces inhibition of the host IFN production and may provide a potential target for antiviral drug development. However, our study demonstrated that the influenza A virus NS1 ED targets TRAF3, subsequently inhibits IFN production, implying that TRAF3 is a key factor involved for IAV to escape host innate immune responses. doi = 10.3389/fimmu.2017.00779 id = cord-305737-bnzd7b25 author = Rehwinkel, Jan title = Targeting the viral Achilles’ heel: recognition of 5′-triphosphate RNA in innate anti-viral defence date = 2013-05-23 keywords = RNA; figure; rig summary = Targeting the viral Achilles'' heel: recognition of 5 0 -triphosphate RNA in innate anti-viral defence Jan Rehwinkel 1 and Caetano Reis e Sousa 2 Some RNA virus genomes bear 5 0 -triphosphates, which can be recognized in the cytoplasm of infected cells by host proteins that mediate anti-viral immunity. Both the innate sensor RIG-I and the interferon-induced IFIT proteins bind to 5 0 -triphosphate viral RNAs. RIG-I signals for induction of interferons during RNA virus infection while IFITs sequester viral RNAs to exert an antiviral effect. Recent work shows that the IFN system targets 5PPP RNAs during both phases: both RIG-I, a virus sensor that induces IFN expression, and IFITs, effector molecules that execute anti-viral activities, can specifically recognize 5PPP RNAs. As such, 5PPP RNAs appear to be Achilles'' heel of many RNA viruses in their interaction with the innate immune system (Figure 3a ). doi = 10.1016/j.mib.2013.04.009 id = cord-341324-f9g9gitn author = Rojas, José M. title = Viral pathogen-induced mechanisms to antagonize mammalian interferon (IFN) signaling pathway date = 2020-10-21 keywords = IFN; IRF3; PRR; RNA; protein; rig; virus summary = This includes for instance cooperating in PRR recognition of viral PAMPs, stabilizing signaling complexes to improve their resistance to degradation, stopping virus entry, blocking viral capsid formation, impairing trafficking and budding of virions from the infected cells, but also modulating the IFN response to avoid the toxicity of these potent immune mediators. The phosphorylated STAT1/STAT2 heterodimer associates with interferon regulatory factor 9 (IRF9) to form the transcriptional factor complex ISGF3, which translocate to the nucleus and binds the IFN-response elements (ISRE) in ISG promoters leading to the expression of ISG products [36] (Fig. 2 The oligoadenylate synthetase (OAS)-latent RNase (RNase L) pathway is another IFN-inducible pathway that provides the cell with an effector mechanism upon recognition of viral dsRNA (reviewed in [44] ). doi = 10.1007/s00018-020-03671-z id = cord-007689-0vpp3xdl author = Schlee, M. title = Beyond Double-Stranded RNA-Type I IFN Induction by 3pRNA and Other Viral Nucleic Acids date = 2007 keywords = IFN; RNA; rig summary = Since the discovery of type I IFNs in 1957, long double-stranded RNA formed during replication of many viruses was thought to be responsible for type I IFN induction, and for decades double-stranded RNA-activated protein kinase (PKR) was thought to be the receptor. It now became evident that not PKR but two members of the Toll-like receptor (TLR) family, TLR7 and TLR9, and two cytosolic helicases, RIG-I and MDA-5, are responsible for the majority of type I IFNs induced upon recognition of viral nucleic acids. Based on the recent progress in the field, we now know that TLR7, TLR9, and RIG-I do not require long double-stranded RNA for type I IFN induction. These two cytosolic receptors are then responsible for the second and prolonged wave of type I IFN production and for the induction of apoptosis of virally infected cells. Small interfering RNAs mediate sequence-independent gene suppression and induce immune activation by signaling through toll-like receptor 3 doi = 10.1007/978-3-540-71329-6_11 id = cord-307598-p54p7enk author = Schlee, Martin title = Master sensors of pathogenic RNA – RIG-I like receptors date = 2013-07-01 keywords = CTD; IFN; MDA5; RNA; rig summary = Similar to TLRs, RIG-I and MDA5 induce type I IFN and chemokines (but no IL12) upon activation by viral but also bacterial RNA. Since type I IFN induction by this RNA required RNase L, the authors concluded that RNase L recognizes and processes viral mRNA into a MDA5 activating structure. Before 5 triphosphate was identified as the crucial RNA modification to induce RIG-I activation, Marques and colleagues observed that synthetic blunt ended dsRNA oligonucleotides can stimulate RIG-I ( Fig. 3 ) (Marques et al. (2010b) confirmed the requirement of a base paired 5 -ppp end of dsRNA for RIG-I activation and suggested that some arenaviruses and bunyaviruses use a prime and realign mechanism for genome synthesis, leading to 5 overhangs in order to evade RIG-I recognition (Marq et al. pneumophilae did not induce type I IFN in HEK293 cells, thus excluding RIG-I-mediated recognition of RNA polymerase-III transcripts in the host cell, as previously suggested (Chiu et al. doi = 10.1016/j.imbio.2013.06.007 id = cord-312075-asbt0mcj author = Schulz, Katharina S. title = Viral Evasion Strategies in Type I IFN Signaling – A Summary of Recent Developments date = 2016-11-11 keywords = IFN; IRF3; TBK1; rig summary = Human T-cell lymphotropic virus type I (HTLV-1) protein Tax disrupts innate immune signaling in multiple ways: it binds to the RIP homotypic interaction motif (RHIM) domains of RIP-1 and disrupts the interaction between RIP-1 and RIG-I or MDA-5 and the activation of the type I IFN promoter. Upon stimulation, TBK1 and IKKε are recruited by adaptor proteins to signaling complexes to be activated by phosphorylation on Ser172 and both have been shown to be subjected to K63-linked polyubiquitination [reviewed in Ref. Interestingly, when a recent study tested how the rabies virus P protein of street strains behaves compared to laboratory-adapted strains with regard to the induction of type I IFN, they found that both street strains and laboratory strains inhibit TBK1-mediated signaling, but only the P protein of street strains also interacts with and inhibits IKKε-inducible IRF3dependent IFNβ expression (88) (Figure 1) . Middle east respiratory syndrome coronavirus M protein suppresses type I interferon expression through the inhibition of TBK1-dependent phosphorylation of IRF3 doi = 10.3389/fimmu.2016.00498 id = cord-355839-o0m71kvw author = Sedeyn, Koen title = Respiratory syncytial virus nonstructural proteins 1 and 2: Exceptional disrupters of innate immune responses date = 2019-10-17 keywords = IFN; NS2; RSV; ns1; rig summary = ATF2, activating transcription factor 2; CDS, cytoplasmic DNA sensor; ER, endoplasmic reticulum; IFN, interferon; IKK, inhibitor of nuclear factor kappa-B kinase; IKKε, inhibitor of nuclear factor kappa-B kinase subunit epsilon; IRF3, interferon regulatory factor 3; IRF7, interferon regulatory factor 7; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MAVS, mitochondrial antiviral-signaling protein; MDA5, melanoma differentiation-associated protein 5; MyD88, myeloid differentiation primary response protein MyD88; NF-kB, nuclear factor-kappa B; NOD2, nucleotide-binding oligomerization domain-containing protein 2; PAMP, pathogenassociated molecular pattern; PRR, pattern recognition receptor; RIG, retinoic-acid-inducible gene-I; RLR, RIG-I-like receptor; RSV, respiratory syncytial virus; STING, stimulator of interferon protein; TBK1, tank binding kinase 1; TICAM1, toll/interleukin-1 receptor domain-containing adapter molecule 1; TIRAP, toll/ interleukin-1 receptor domain-containing adapter protein; TLR, toll-like receptor; TRAF3, tumor necrosis factor receptor-associated factor 3; TRAF6, tumor necrosis factor receptor-associated factor 6; TRAM, toll-like receptor adaptor molecule. doi = 10.1371/journal.ppat.1007984 id = cord-131093-osukknqr author = Suzen, Neslihan title = Informational Space of Meaning for Scientific Texts date = 2020-04-28 keywords = LSC; Meaning; Scientific; Space; category; figure; rig; word summary = We introduce the Meaning Space, in which the meaning of a word is represented by a vector of Relative Information Gain (RIG) about the subject categories that the text belongs to, which can be obtained from observing the word in the text. Informational Space of Meaning for Scientific Texts Poibeau and Korhonen then purposed a model in which latent space is used to identify important dimensions for a context and adapt to vector of words constructed by the dependency relations with window-based context words [69]. This technique allowed us to represent each word by a distribution of numerical values over categories and meaning in text through a vector space model, that is, quantifying of meaning. Therefore, we introduce a new vector space to represent word meaning based on words'' informational importance in the subject categories. Informational Space of Meaning for Scientific Texts a list of words where words are sorted in descending order by their RIGs can be created. doi = nan id = cord-285339-pwy1ry4n author = Tarigan, Ronald title = Role of pattern recognition receptors and interferon-beta in protecting bat cell lines from encephalomyocarditis virus and Japanese encephalitis virus infection date = 2020-06-18 keywords = EMCV; JEV; rig summary = Here, kidney epithelial cell lines derived from four bat species (Pteropus dasymallus, Rousettus leschenaultii, Rhinolophus ferrumequinum, and Miniopterus fuliginosus) and two non-bat species (Homo sapiens and Mesocricetus auratus) were infected with EMCV and JEV. fuliginosus with a higher expression level of pattern recognition receptors (PRRs) (TLR3, RIG-I, and MDA5) and interferon-beta (IFN-β) than that in the non-bat cell lines and a bat cell line derived from P. The knockdown of TLR3, RIG-I, and MDA5 in Rhinolophus bat cell line using antisense RNA oligonucleotide led to decrease IFN-β expression and increased viral replication. EMCV and JEV infection resulted in a higher expression level of PRRs in bat cell lines with a lower viral replication level (DEMKT1, BKT1, and YUBFKT1) (Fig. 2B, C, and 2D ). doi = 10.1016/j.bbrc.2020.04.060 id = cord-319729-6lzjhn8j author = Tian, Bin title = Lab-Attenuated Rabies Virus Causes Abortive Infection and Induces Cytokine Expression in Astrocytes by Activating Mitochondrial Antiviral-Signaling Protein Signaling Pathway date = 2018-01-19 keywords = DRV; RABV; RNA; figure; rig summary = title: Lab-Attenuated Rabies Virus Causes Abortive Infection and Induces Cytokine Expression in Astrocytes by Activating Mitochondrial Antiviral-Signaling Protein Signaling Pathway Activation of mitochondrial antiviral-signaling protein (MAVS), the common adaptor molecule for RIG-I and MDA5, results in the production of type I interferon (IFN) and the expression of hundreds of IFN-stimulated genes, which suppress RABV replication and spread in astrocytes. Activation of mitochondrial antiviral-signaling protein (MAVS), the common adaptor molecule for RIG-I and MDA5, results in the production of type I interferon (IFN) and the expression of hundreds of IFN-stimulated genes, which suppress RABV replication and spread in astrocytes. To assess innate immune responses in astrocytes, cells were infected with DRV or B2c at an MOI of 0.1 and the expression of several proteins involved in the MAVS signaling pathway, namely, RIG-I, p-IRF7, STAT1 and IFIT1 (ISG56), was measured by Western blot. doi = 10.3389/fimmu.2017.02011 id = cord-323756-atnrw9ew author = Vabret, Nicolas title = Sensing Microbial RNA in the Cytosol date = 2013-12-25 keywords = IFN; MDA5; RNA; rig summary = When Janeway formulated the theory of pattern recognition in 1989, he proposed that host cells could sense microbial infection owing to receptors able to recognize invariant molecular structures defined as pathogen-associated molecular patterns (PAMPs). They share a similar organization with three distinct domains: (i) a C-terminal repressor domain (RD) embedded within the C-terminal domain (CTD); (ii) a central ATPase containing DExD/H-box helicase domain able to bind RNA; and (iii) a N-terminal tandem CARD domain that mediates downstream signaling, and which is present in RIG-I and MDA5 but absent in LGP2. DDX60 has also been shown to enhance the IFN-I response to RNA and DNA stimulation through formation of complexes with Frontiers in Immunology | Molecular Innate Immunity RIG-I, MDA5, and LGP2 but not with MAVS. Structural basis for the activation of innate immune pattern-recognition receptor RIG-I by viral RNA Nonself RNA-sensing mechanism of RIG-I helicase and activation of antiviral immune responses doi = 10.3389/fimmu.2013.00468 id = cord-342653-bpyc2gbl author = Wang, Hai-Tao title = Substrate recognition by TRIM and TRIM-like proteins in innate immunity date = 2020-10-20 keywords = MAVS; RNA; rig; trim summary = While E3 ligases are often thought to negatively regulate the stability of the target molecule by Ub-mediated proteasomal targeting, many TRIMs have been shown to enhance innate immune signaling pathways [15] , through both proteasome-dependent and -independent mechanisms. The study of RIG-I and RIPLET interaction provides a detailed example of how TRIM-like proteins utilize bivalency and CC for regulating substrate selectivity, higher-order oligomerization and innate immune function. Given that an increasing number of receptors and signaling molecules in the innate immune system are shown to multimerize upon activation [77] , it is tempting to speculate that TRIM/TRIM-like proteins may utilize multimer-specific substrate recognition as a common mechanism for regulating their immune functions. The avidity-driven substrate recognition mechanism of TRIM/TRIM-like proteins would thus ensure more precise control of innate immune signaling and restriction functions. doi = 10.1016/j.semcdb.2020.09.013 id = cord-319501-a2x1hvkk author = Wong, Lok-Yin Roy title = A molecular arms race between host innate antiviral response and emerging human coronaviruses date = 2016-01-15 keywords = IFN; MERS; RNA; SARS; rig summary = Particularly, the host pathogen recognition receptors and the signal transduction pathways to mount an effective antiviral response against SARS and MERS coronavirus infection are discussed. This suggests SARS-CoV N may interfere with RNA recognition by host immune sensors such as RIG-I and MDA5 thus achieving suppressive role in IFN production. Our group demonstrated that MERS-CoV ORF4a interacts with PACT, a cellular dsRNA-binding protein that optimally activates RIG-Iand MDA5-induced type I IFN production, in an RNAdependent manner (Siu et al., 2014c) . Infection with SARS-CoV and MERS-CoV has been accompanied with suppression of innate immune response, most notably with the suppression of type I IFN production and signaling pathways. Severe acute respiratory syndrome coronavirus nsp1 suppresses host gene expression, including that of type I interferon, in infected cells Middle East respiratory syndrome coronavirus 4a protein is a double-stranded RNA-binding protein that suppresses pact-induced activation of RIG-I and MDA5 in the innate antiviral response doi = 10.1007/s12250-015-3683-3 id = cord-343963-99rd3o79 author = Wong, Mun-Teng title = Emerging roles of interferon-stimulated genes in the innate immune response to hepatitis C virus infection date = 2014-12-29 keywords = HCV; IFN; NS5A; PKR; RNA; rig; table; virus summary = 13, 14 Upon infection by viruses such as HCV, viral RNA is first sensed by cellular pattern recognition receptors (PRRs), and the PRR-mediated recruitment of adaptor proteins and the activation of downstream signaling lead to IFN production. First, we briefly discuss the signaling triggered by the retinoic acid-inducible gene 1-like receptor (RLR) and the Toll-like receptor (TLR), which leads to type I IFN synthesis and IFN-mediated signaling pathway activation, resulting in the expression of a variety of effector ISGs. We also summarize the strategies that HCV uses to escape IFN antiviral surveillance. 156 demonstrated that HCVinduced SG formation is IFN-and PKR-dependent and is inversely correlated with the induction of ISG proteins, such as myxovirus resistance gene A (MxA) and Ub-like (UBL)specific protease 18 (USP18), in HCV-infected cells without affecting the mRNA levels of these ISGs. Furthermore, the SG proteins TIA-1, TIAR and G3BP1 have been shown to play a critical role in HCV replication and infectious virus production. doi = 10.1038/cmi.2014.127 id = cord-306533-lvm11o4r author = Woo, Bean title = Regulatory interplay between deubiquitinating enzymes and cytokines date = 2019-06-08 keywords = HEK293; IFN; USP25; dub; rig summary = DUBs interact with some of the key molecules in the IFN signaling pathway, which include, but are not limited to, RIG-I, stimulator of interferon genes (STING), tumor necrosis factor receptor-associated factors (TRAFs), interferon regulatory factor are summarized in Table 1 . A study conducted using human kidney mesangial cells (MC) showed slightly different results: silencing CYLD in MC cells and stimulating them with poly IC increased the toll-like receptor 3 (TLR3)-induced activation of RIG-I and MDA5 [26] ; however, the level of mRNA of RIG-I and MDA5 actually decreased [26] . However, when USP18 -/-MEF cells with either WT USP18 or DUB activity-mutated USP18 were induced with HSV-1, HCMV or cytosolic DNA, Ifnb, Ifna4, Tnf, IL-6 or Cxcl1 genes increased in expression, indicating that the deubiquitinating activity of USP18 is not responsible for this phenomenon [41] . In a study by Malakhova et al., USP18 inhibited IFN-induced gene activation by affecting JAK-STAT signaling pathway in 293 T cells [44] . doi = 10.1016/j.cytogfr.2019.06.001 id = cord-299964-sn5o3ugb author = Xue, Qiao title = Seneca Valley Virus 3C protease negatively regulates the type I interferon pathway by acting as a viral deubiquitinase date = 2018-11-05 keywords = SVV; TBK1; rig summary = Furthermore, 3C(pro) inhibited the ubiquitination of retinoic acid-inducible gene I (RIG-I), TANK-binding kinase 1 (TBK1), and TNF receptor-associated factor 3 (TRAF3), thereby blocking the expression of interferon (IFN)-β and IFN stimulated gene 54 (ISG54) mRNAs. A detailed analysis revealed that mutations (H48A, C160A, or H48A/C160A) that ablate the Cys and His residues of 3C(pro) abrogated its deubiquitinating activity and the ability of 3C(pro) to block IFN-β induction. To determine whether SVV can evade innate immune response by inhibiting the host ubiquitination, HEK293T cells were transfected with FLAG-tagged VP1, VP2, 2AB, 2B, 2C, 3D, 3C plasmids along with HA-Ub plasmid. As shown in Fig. 1A , expression of 3C pro resulted in a dose-dependent reduction of the level of ubiquitinated cellular proteins compared with that in the empty vector-transfected cells. Taken together, these results indicate that SVV and 3C pro inhibit the ubiquitination of RIG-I, TBK1, and TRAF3 in a DUB-dependent manner. doi = 10.1016/j.antiviral.2018.10.028 id = cord-252485-cxi3cr15 author = Yoshida, Asuka title = IFN-β-inducing, unusual viral RNA species produced by paramyxovirus infection accumulated into distinct cytoplasmic structures in an RNA-type-dependent manner date = 2015-08-04 keywords = IFN; RNA; figure; rig summary = We and other groups have recently reported that recombinant viruses of Sendai virus (SeV), a prototype of the family Paramyxoviridae, in which the C proteins are knocked-out or mutated, generate dsRNA in infected cells at levels similar to the production of IFN-β (Takeuchi et al., 2008; Irie et al., 2010) . These unusual RNAs exhibited distinct properties in infected cells in terms of encapsidation with the viral N protein and subcellular distribution with SG marker proteins and RLRs. Our results suggest that RNA-typedependent mechanisms recognize and accumulate virus-derived, IFN-β-inducible, unusual RNAs into specific compartment to trigger the production of IFN-β, and that SeV may evade detection by the host innate immune system by preventing the production of these RNA species. Since the naked cbDI genomes have been reported readily to form an ideal structure as the RIG-I ligands of 5 -triphosphated, blunt-ended dsRNA (Kolakofsky, 1976) , these results indicated that the major IFN-β-inducing viral RNA species produced in the cells infected with CNT was encapsidated cbDI genomes, whereas those for SeV-4C(-) and NDV were not. doi = 10.3389/fmicb.2015.00804 id = cord-257886-ytlnhyxr author = Zhao, Kuan title = Nucleocapsid protein of porcine reproductive and respiratory syndrome virus antagonizes the antiviral activity of TRIM25 by interfering with TRIM25-mediated RIG-I ubiquitination date = 2019-05-03 keywords = PRRSV; TRIM25; rig summary = title: Nucleocapsid protein of porcine reproductive and respiratory syndrome virus antagonizes the antiviral activity of TRIM25 by interfering with TRIM25-mediated RIG-I ubiquitination These results indicate for the first time that TRIM25 inhibits PRRSV replication and that the N protein antagonizes the antiviral activity by interfering with TRIM25-mediated RIG-I ubiquitination. The cells were lysed in RIPA lysis buffer after 36 h of transfection and the effects of siRNAs were analyzed by WB using an anti-TRIM25 monoclonal antibody (cat. To investigate whether TRIM25-mediated RIG-I ubiquitination is regulated by the PRRSV N protein, HEK293T cells grown in 6-well plates were co-transfected with pCAGGS-Flag-RIG-I (0.5 μg per well) and HA-ubiquitin (0.5 μg per well), and the indicated amounts of the Myc-N expression plasmids. The experiment revealed that TRIM25-mediated RIG-I ubiquitination was potentiated by Sendai virus (SEV) infection but was substantially suppressed by increasing the PRRSV N protein expression, in a dose-dependent manner (Fig. 5) . doi = 10.1016/j.vetmic.2019.05.003 id = cord-351520-c5fi2uoh author = Zhong, Bo title = Regulation of virus-triggered type I interferon signaling by cellular and viral proteins date = 2010-02-01 keywords = IFN; IRF3; RNA; TBK1; rig summary = Recently, we and others identified a new adapter protein called mediator of IRF3 activation (MITA, also known as STING), which plays a critical role in virus-induced type I IFN expression (Ishikawa and Barber, 2008; Zhong et al., 2008) . doi = 10.1007/s11515-010-0013-x id = cord-278523-djjtgbh6 author = Zhou, Bei-xian title = β-sitosterol ameliorates influenza A virus-induced proinflammatory response and acute lung injury in mice by disrupting the cross-talk between RIG-I and IFN/STAT signaling date = 2020-06-05 keywords = Fig; IAV; IFN; rig summary = We demonstrate that β-sitosterol (150–450 μg/mL) dose-dependently suppresses inflammatory response through NF-κB and p38 mitogen-activated protein kinase (MAPK) signaling in influenza A virus (IAV)-infected cells, which was accompanied by decreased induction of interferons (IFNs) (including Type I and III IFN). Furthermore, we revealed that the anti-inflammatory effect of β-sitosterol resulted from its inhibitory effect on retinoic acid-inducible gene I (RIG-I) signaling, led to decreased STAT1 signaling, thus affecting the transcriptional activity of ISGF3 (interferon-stimulated gene factor 3) complexes and resulting in abrogation of the IAV-induced proinflammatory amplification effect in IFN-sensitized cells. Together, these data demonstrate that β-sitosterol blocks the IAV-induced amplification of the proinflammatory response in IFN-β-activated A549 cells, which is due to inhibition of RIG-I levels by β-sitosterol, leading to the inactivation of STAT1, and thereby diminishes the transcriptional activity of interferon-stimulated gene factor 3 (ISGF3). doi = 10.1038/s41401-020-0403-9 id = cord-299754-tgexahwd author = van Tol, Sarah title = The TRIMendous Role of TRIMs in Virus–Host Interactions date = 2017-08-22 keywords = HIV-1; IFN; RLR; RNA; TRIM25; rig; trim summary = Downstream of the initial pattern recognition, TRIMs also influence the recruitment and interaction of adaptor molecules (stimulator of IFN genes (STING), mitochondrial antiviral signaling protein (MAVS), TGF-β-activated kinase 1(TAK1)/MAP3K7-binding protein (TAB) 2, Myeloid differentiation primary response gene 88 (MyD88), TIR-domain-containing adapterinducing interferon-β (TRIF), NF-κB essential modulator (NEMO), nucleosome assembly protein (NAP-1), and tumor necrosis factor (TNF) receptor-associated factors (TRAF) family memberassociated NF-κB activator (TANK)) and enzymes (TRAF3, TRAF6, TAK1, inhibitor of NF-κB (IκB) kinase (IKK) α,β,ε, TANK binding kinase 1 (TBK1)) to signaling complexes in order to activate transcription factors. Downstream of the initial pattern recognition, TRIMs also influence the recruitment and interaction of adaptor molecules (stimulator of IFN genes (STING), mitochondrial antiviral signaling protein (MAVS), TGF-β-activated kinase 1(TAK1)/MAP3K7-binding protein (TAB) 2, Myeloid differentiation primary response gene 88 (MyD88), TIR-domain-containing adapter-inducing interferon-β (TRIF), NF-κB essential modulator (NEMO), nucleosome assembly protein (NAP-1), and tumor necrosis factor (TNF) receptor-associated factors (TRAF) family member-associated NF-κB activator (TANK)) and enzymes (TRAF3, TRAF6, TAK1, inhibitor of NF-κB (IκB) kinase (IKK) α,β,ε, TANK binding kinase 1 (TBK1)) to signaling complexes in order to activate transcription factors. doi = 10.3390/vaccines5030023