key: cord-312886-o3ipzn05
authors: Onomoto, Koji; Yoneyama, Mitsutoshi; Fung, Gabriel; Kato, Hiroki; Fujita, Takashi
title: Antiviral innate immunity and stress granule responses
date: 2014-08-19
journal: Trends Immunol
DOI: 10.1016/j.it.2014.07.006
sha: 
doc_id: 312886
cord_uid: o3ipzn05

Viral infection triggers the activation of antiviral innate immune responses in mammalian cells. Viral RNA in the cytoplasm activates signaling pathways that result in the production of interferons (IFNs) and IFN-stimulated genes. Some viral infections have been shown to induce cytoplasmic granular aggregates similar to the dynamic ribonucleoprotein aggregates termed stress granules (SGs), suggesting that these viruses may utilize this stress response for their own benefit. By contrast, some viruses actively inhibit SG formation, suggesting an antiviral function for these structures. We review here the relationship between different viral infections and SG formation. We examine the evidence for antiviral functions for SGs and highlight important areas of inquiry towards understanding cellular stress responses to viral infection.

Viral infection triggers the activation of antiviral innate immune responses in mammalian cells. Viral RNA in the cytoplasm activates signaling pathways that result in the production of interferons (IFNs) and IFN-stimulated genes. Some viral infections have been shown to induce cytoplasmic granular aggregates similar to the dynamic ribonucleoprotein aggregates termed stress granules (SGs), suggesting that these viruses may utilize this stress response for their own benefit. By contrast, some viruses actively inhibit SG formation, suggesting an antiviral function for these structures. We review here the relationship between different viral infections and SG formation. We examine the evidence for antiviral functions for SGs and highlight important areas of inquiry towards understanding cellular stress responses to viral infection. 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. Several innate immune sensors recognize cytoplasmic viral RNA [1] , and lead to the production of IFNs which in turn trigger various antiviral pathways aimed at halting viral replication and spread. These antiviral effects include double-stranded (ds) RNAdependent protein kinase (PKR)-dependent inhibition of mRNA translation, and 2 0 ,5 0 -oligoadenylate synthetase (OAS)/RNase L-mediated RNA degradation [2] . Innate immune responses also trigger the activation of adaptive immunity in the form of T and B cell activation and proliferation, and modulate the phenotype and function of these adaptive responses [3, 4] .

In some cases, viral infection also induces the formation of cytoplasmic granules similar to those induced by cellular stresses such as heat, oxidation, hypoxia, and osmotic pressure, which are referred to as stress granules (SGs). SGs are ribonucleoprotein (RNP) aggregates that contain translationally stalled mRNAs, 40S ribosomes, and various RNA-binding proteins [5] [6] [7] (Box 1).

Activation of the RLR signaling pathways by viral RNA Innate immune responses are triggered upon recognition of pathogen-associated molecular patterns (PAMPs) which in the case of viruses are often nucleic acid-based, either RNA or DNA. Viral nucleic acid can be detected by sensors including Toll-like receptors (TLR)3, 7/8, and 9, retinoic acid inducible gene I (RIG-I)-like receptors (RLRs), and cytoplasmic DNA sensors such as DNA-dependent activator of IFN-regulator factors (DAI), stimulator of IFN genes (STING, also known as MITA/ERIS/MPYS), DEAD box polypeptide 41 (DDX41), and cGMP/cAMP synthase (cGAS) [8] [9] [10] [11] [12] . RLRs, RIG-I, melanoma differentiationassociated protein 5 (MDA5), and DHX58 [DEXH (Asp-Glu-X-His) box polypeptide 58, also known as LGP2] are all RNA helicases and contain the signature DExD/H motif that characterized the DExD/H box family. These proteins are crucial for the detection of cytoplasmic RNA [13, 14] . RLRs discriminate self from viral transcripts by recognizing specific biochemical signatures such as ds structure and the presence of a 5 0 -ppp moiety [15] [16] [17] ; self-transcipts lack these viral signatures.

The signaling pathways downstream of the founding member of the RLR family, RIG-I, are among the best understood. Upon viral RNA recognition by RIG-I, the signal is relayed to the adaptor protein IFN-b promoter stimulator 1 (IPS-1, also known as MAVS, VISA, or Cardif), which predominantly localizes to the mitochondrial outer membrane [18, 19] . When viral RNA binds at the helicase and the C-terminal domain (CTD) of RIG-I, its N-terminal caspase recruitment domains (CARDs) are covalently modified with K63-linked polyubiquitin chains by the E3 ligase, tripartite motif-containing protein 25 (TRIM25) [20] , and oligomerize [21] . The ubiquitinated and oligomerized CARDs bind to the CARD domain on IPS-1 on mitochondria, peroxisomes, and/ or mitochondrion-associated membrane (MAM) regions in the endoplasmic reticulum (ER) [22] . The translocation of RIG-I to these locales is facilitated by the chaperone protein 14-3-3e [23] . The requirement for K63-linked polyubiquitin chains is complex because several reports have demonstrated the importance of non-covalent interaction between RIG-I CARDs and the unanchored K63-ubiquitin chains [21, 24] . Box 1. An overview of SG biology Cells respond to various insults including heat, oxidative stress, nutrient starvation, and proteotoxic stress by forming cytoplasmic nucleoprotein aggregates termed SGs [5, [68] [69] [70] . Multiple RNAbinding proteins (RBPs) localize to SGs, and some have been used as markers for these cytoplasmic bodies (Table I) . Although the formation of SGs in live cells can be detected by monitoring fluorescence-tagged SG marker proteins, biochemical isolation of SGs is notoriously challenging because these are not membranesequestered compartments.

SG formation has been interpreted as a response aimed at preventing the generation of abnormal proteins by transient stalling of translation in times of cellular stress. Stalled transcripts undergo translation upon recovery from stress, or alternatively they are degraded in another granular compartment termed the processing body (P-body, PB) [71, 72] . Unlike SGs, PBs are present in the unstressed cell, and contain enzymes for mRNA degradation such as decapping enzymes and 5 0 -3 0 exonucleases (Table I ). It is thought that transcripts and proteins can move from SGs to PBs (and vice versa), and these aggregates share some of their components (Table  I) [60] ; however, the mechanisms underlying the proposed exchange of contents are unclear.

SG proteins, as defined by studies using proteins characteristic to SGs as markers [73] , are either diffusely distributed in the cytoplasm or localized in the nucleus in normal conditions; stress triggers their aggregation in the cytoplasm [5, 74] . A common event downstream from the aforementioned cellular stresses is phosphorylation of eIF2a at serine 51, which is considered to be an initial trigger for SG formation. Four eIF2a kinases, PKR, GCN2, PKR-like endoplasmic reticulum kinase (PERK), and heme-regulated eIF2a kinase (HRI), can phosphorylate eIF2a in mammals (Table II) . The mechanisms that connect eIF2a phosphorylation to SG formation remain to be elucidated.

Some proteins have been shown to be crucial for the formation and or stability of SGs. These include G3BP1, a phosphorylationdependent endonuclease [30, 75] , and T cell restricted intracellular antigen-1 (TIA1) and TIA-related protein (TIAR) that are collectively termed TIA1/TIAR [74, 76] . Removal of these regulators by genomic deletion or RNAi blocks SG formation by sodium arsenite, and a mutant form of G3BP1 (S149E) acted as a dominant inhibitor of SG formation [75] . However, because of analytical constraints, the molecular machinery underlying the formation of SGs remains unclear. Furthermore, it has been reported that RIG-I forms a signaling-competent filament on substrate dsRNA independently of ubiquitins [25] . Although a recent structural report suggests that the conformation of the active tetramer of RIG-I CARDs can be stabilized by covalent conjugation with ubiquitin chains, and that filament formation may partially compensate for ubiquitin-dependent RIG-I activation [26] , further analysis will be necessary to clarify the molecular role of ubiquitin chains in RIG-I signaling. The RIG-I/IPS-1 interaction recruits signaling molecules including tumor necrosis factor (TNF) receptor-associated factors (TRAFs). Subsequent activation of TANK-binding kinase 1(TBK1)/inducible IkB kinase (IKKi), and IKKa/IKKb induces downstream signaling via the IFN regulatory factor (IRF) and nuclear factor-kB (NF-kB) pathways, respectively. These pathways ultimately culminate in the activation of the transcription factors IRF-3, IRF-7, and NF-kB, which activate the transcription of IFN and proinflammatory cytokine genes [27] . These pathways are summarized in Figure 1 . Moreover, secreted IFN amplifies the expression of ISGs, such as RLRs, PKR, and OAS, as a host strategy to amplify antiviral signaling.

Viruses, particularly RNA viruses, have been shown to induce the formation of SG-like cytoplasmic bodies (Table 1 

Trends in Immunology September 2014, Vol. 35, No. 9 and references therein). 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 ). Depending on both the virus and the host cell, different patterns of SG formation have been observed upon infection: stable SG formation, no SG formation, transient SG formation, or alternating (oscillating) SG formation in which SGs form, disperse, and reform during the assays (Table 1) . Transient SG formation results from dissociation of key components in SGs by viral proteins [29] [30] [31] [32] [33] . For instance, in the case of infection of several picornaviruses, such as poliovirus, coxsackievirus and encephalomyocarditis virus (EMCV), transient formation of SGs is associated with the cleavage of Ras-GAP SH3 domain binding protein-1 (G3BP1) by the viral 3C protease [29] [30] [31] . This was confirmed by the observation that ectopic expression of cleavage-resistant G3BP1 leads to stable SG formation. On the other hand, recent studies have demonstrated that infection with hepatitis C virus (HCV) produces oscillating SGs [34] . HCV strongly activates PKR via the 5 0 -untranslated region (UTR) of its genome [35] , thereby inducing SGs [34, 36] , but stress-inducible expression of growth arrest DNA-damageinducible 34 (GADD34), a regulatory component of host protein phosphatase 1 (PP1), leads to dephosphorylation of eIF2a and terminates SG formation. 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. Cells infected with mengovirus or Theiler's murine encephalomyelitis virus (TMEV), which belong to the Cardiovirus genus within the family of Picornaviridae, do not exhibit SGs, and this has been proposed to be due to complete inhibition of SG formation by the viral nonstructural protein, leader (L) protein [37] . Although L protein is known to block IFN production via inhibition of IRF-3 activation [38] , it remains unknown how L limits SG formation.

Similarly, SGs do not form upon infection of cells with measles virus. In this case the mechanism proposed involves the viral C protein because C-deficient virus, but not the wild type, strikingly induces SGs [39] . Although measles C protein has diverse functions during infection, including modulation of viral polymerase activity and inhibition of IFN production [40] , the molecular machinery for SG inhibition remains to be determined. In virus-infected cells, viral RNAs activate PKR (or GCN2, in the case of Sindbis virus) to initiate assembly of SG through eIF2a phosphorylation. eIF2a phosphorylation blocks translation of cellular mRNAs. Translation-stalled mRNAs may be transferred to a distinct cellular compartment, the P-body, to be degraded. Viral RNAs are also recognized by RLRs, which are recruited to SGs with several signaling molecules including antiviral proteins and ubiquitin ligases. The OAS-RNase L pathway cleaves viral RNAs, and the cleaved RNAs may act as ligands for RLRs. IPS-1, which is localized on mitochondria and/or MAM, forms prion-like aggregates, interacts with RLRs on SGs, and activates IFN-inducing signaling. Areas that require further investigation are highlighted with question marks.

Trends in Immunology September 2014, Vol. 35, No. 9 In the case of influenza A virus (IAV), the viral nonstructural protein 1(NS1) has been shown to inhibit eIF2a phosphorylation by blocking PKR activation via viral RNA sequestration and physical interaction [41] [42] [43] . During IAV infection, the viral nucleocapsid initially accumulates in the nucleus and is then transported to the cytoplasm in the late phase of infection. However, in a mutant IAV lacking NS1, the viral nucleocapsid was reported to coincide with SGs in the cytoplasm, to which RIG-I is colocalized [42] . These findings suggest that SGs function as a platform for the detection of IAV genomic RNA by RIG-I.

As in the cases of mengovirus, TMEV, and measles virus, there appears to be a clear benefit, from the standpoint of the virus, to interfering with SG formation. An implication of these findings is that SGs have an antiviral role and that, accordingly, viruses have developed strategies to suppress their formation ( Figure 2) . Indeed, there are multiple examples of viruses actively inhibiting the formation of SGs through varied mechanisms [44] [45] [46] [47] [48] . An inverse correlation between SG formation and viral propagation has been reported in multiple viral replication systems. In the case of Japanese encephalitis virus (JEV) infection, SG formation is inhibited by the viral core protein, which directly interacts with SG component, caprin 1 [44] . In cells infected with a mutant virus whose core protein fails to interact with caprin 1, inhibition of SG formation is abrogated and viral propagation is significantly impaired both in vitro and in vivo, suggesting that SGs impact negatively on viral replication. This notion is further supported by studies showing that RLRs localize to virus-induced SGs, suggesting that SGs may act as a platform for viral RNA sensing and the activation of downstream signaling pathways [42] . There is a strong correlation between PKR-dependent SG formation and IFN production in some viral infections [29, 42, 49] (Figure 2 ). However, a recent study has demonstrated that PKRdependent accumulation of MDA5 in SGs is dispensable for triggering IFN responses [50] . Further investigations will be necessary to address this discrepancy.

Whether PKR is required for virus-induced IFN production is controversial. Some reports indicate that IFN production is significantly impaired in PKR-deficient cells [29, 42, 49, [51] [52] [53] [54] [55] , whereas others show that deficiency of PKR has no effect [54, [56] [57] [58] . One possible explanation for these observations is that there are differences in the viruses and cell types used in each study. In the early 2000s, several studies demonstrated that virus-induced activation of IFN is independent of PKR in plasmacytoid dendritic cells (pDCs), which are known to be 'IFN-producing cells'. However, subsequent reports revealed that robust IFN induction by pDCs is exclusively induced by TLRs, suggesting a dispensable role for PKR in TLRmediated signaling. By contrast, the PKR-dependency of RLR-mediated signaling is more complicated. Because viruses are extraordinary diverse in their genome structures and life cycles, different viruses are likely to produce different RNA species during viral replication at distinct locations in the infected cells. Thus, the ability of these viral RNAs to activate PKR and/or RLRs could be divergent. Moreover, as mentioned above, viruses employ a variety of strategies to terminate antiviral responses.

For instance, it has been demonstrated that Sendai virus (SeV)-induced IFN production is independent of PKR [53, 54] . Indeed, infection of SeV can activate IFN without SG formation [29] ; however, infection by a mutant virus in which accessory protein C is deleted leads to significant activation of PKR and eIF2a phosphorylation, with concomitant upregulation of IFN [45, 59] , suggesting that PKR is dispensable for SeV-induced IFN activation, but is responsible for the enhancement of IFN production. Thus, the PKR-dependency of IFN production might vary depending on the ability of each virus to modulate host responses. This notion is supported by reports in which IFN production following stimulation with a virus-mimetic synthetic dsRNA such as poly(I:C) showed significant PKR-dependency [29, 42, 49, 53, 55] .

Understanding the relationship between mechanisms of viral detection and SGs During viral infection, viral RNA, either incoming or produced as a replication intermediate, triggers a series of events. DsRNA activates PKR (or GCN2) to initiate assembly of SG via eIF2a phosphorylation, and this in turn blocks translation and leads to the recruitment of stalled transcripts into SGs (Box 1 and Figure 2 ). It has been proposed that, if the stress stimulus is not resolved, the stalled transcripts are transferred to processing bodies (P-bodies, PBs) for degradation [60] . This view requires reexamination because SG formation does not necessarily result in translational shut-off. Indeed, it is unclear whether SG formation results in total host cell translational shut-off or translational arrest at limited areas in the cytoplasm. Many viruses hijack host cellular compartments to form replication complexes for viral transcription and translation [61, 62] . The fact that IFN is efficiently translated in virus-infected and SG-containing cells [29, 42, 49] suggests that SG formation does not necessarily correlate with total host translational shut-off. Viral dsRNA contained in SG potentially activates OAS to catalyze the synthesis of 2 0 -5 0 oligo A, which activates cytoplasmic endoribonuclease RNase L [63] . RNase L is also detected in SGs of virus-infected cells [42] . Activated RNase L may cleave viral RNA in SG to block viral transcription and translation, and some cleavage products may act as ligands for RLR [64] . Several ubiquitin ligases including TRIM25, RING finger protein leading to RIG-I activation (Riplet), and mex-3 RNA binding family member (MEX3C), that are known to regulate RIG-I activation, are also colocalized in virus-induced SG ( Figure 2) [65, 66] .

Although several studies suggest that RLR might be activated in virus-induced SGs [29, 42, 49] , direct evidence to this effect is lacking. RLR-mediated signaling is transmitted via homotypic interaction with IPS-1, which is localized on mitochondria, peroxisomes, and MAMs. It is unclear how RLR-containing SGs can communicate with these organelles and activate antiviral signaling ( Figure 2) .

A major challenge for SG research is that SGs are difficult entities to isolate for biochemical analyses. The composition of SGs induced by different viruses and in different host cells may vary [49, 67] . The development of novel biochemical isolation approaches and molecular probes for cell biological Review Trends in Immunology September 2014, Vol. 35, No. 9 analyses will be crucial in investigating the molecular events taking place in SGs during viral infection.

Stress responses are known to be crucial for maintaining the homeostasis of living organisms. In response to various stresses, eukaryotic cells initiate stress responses, including the formation of SGs, in which cytoplasmic mRNAs are compartmentalized to escape dysregulation. Accumulated lines of evidence show that viral infection can also induce stress responses including SG formation concurrently with the initiation of innate antiviral responses via pattern recognition receptors (PRRs). The observations that (i) there is a strong correlation between SG formation and IFN production, (ii) there is a reverse correlation between SG formation and viral propagation, and (iii) RLRs are localized in viral-induced SGs together with viral non-self RNAs, together strongly suggest that SGs have an antiviral role and possibly function as platform to initiate innate responses. Interestingly, this notion clearly indicates that the quality control machinery for 'self RNA' and the host defense mechanism against invasion of 'non-self RNA' are closely coordinated with each other. Moreover, it is interesting to note that these observations may help us to develop a novel therapeutic or preventive strategy for virus-induced infectious diseases.

Innate immune detection of microbial nucleic acids

Interferon-inducible antiviral effectors

Regulation of adaptive immunity by the innate immune system

Innate receptors for adaptive immunity

Evidence that ternary complex (eIF2-GTP-tRNA(i)(Met))-deficient preinitiation complexes are core constituents of mammalian stress granules

Stress granules: sites of mRNA triage that regulate mRNA stability and translatability

RNA granules: posttranscriptional and epigenetic modulators of gene expression

The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors

RIG-I like receptors and their signaling crosstalk in the regulation of antiviral immunity

Innate recognition of viruses

Innate immune responses to DNA viruses

cGAS produces a 2 0 -5 0 -linked cyclic dinucleotide second messenger that activates STING

The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses

Shared and unique functions of the DExD/ H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity

Recognition of 5 0 triphosphate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus

0 -Triphosphate RNA requires base-paired structures to activate antiviral signaling via RIG-I

0 -Triphosphate RNA is the ligand for RIG-I

IPS-1, an adaptor triggering RIG-I-and Mda5-mediated type I interferon induction

Orchestrating the interferon antiviral response through the mitochondrial antiviral signaling (MAVS) adapter

TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity

Ubiquitin-induced oligomerization of the RNA sensors RIG-I and MDA5 activates antiviral innate immune response

Mitochondrial-associated endoplasmic reticulum membranes (MAM) form innate immune synapses and are targeted by hepatitis C virus

The mitochondrial targeting chaperone 14-3-3epsilon regulates a RIG-I translocon that mediates membrane association and innate antiviral immunity

Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity

RIG-I forms signaling-competent filaments in an ATP-dependent, ubiquitin-independent manner

Structural basis for ubiquitin-mediated antiviral signal activation by RIG-I

Type I interferon gene induction by the interferon regulatory factor family of transcription factors

Antiviral effect of the mammalian translation initiation factor 2alpha kinase GCN2 against RNA viruses

Encephalomyocarditis virus disrupts stress granules, the critical platform for triggering antiviral innate immune responses

Inhibition of cytoplasmic mRNA stress granule formation by a viral proteinase

Production of a dominant-negative fragment due to G3BP1 cleavage contributes to the disruption of mitochondriaassociated protective stress granules during CVB3 infection

Mammalian orthoreovirus particles induce and are recruited into stress granules at early times postinfection

Importance of eIF2alpha phosphorylation and stress granule assembly in alphavirus translation regulation

Dynamic oscillation of translation and stress granule formation mark the cellular response to virus infection

Regulation of PKR by HCV IRES RNA: importance of domain II and NS5A

Hepatitis C virus (HCV) induces formation of stress granules whose proteins regulate HCV RNA replication and virus assembly and egress

The leader protein of cardioviruses inhibits stress granule assembly

The mengovirus leader protein blocks interferon-alpha/beta gene transcription and inhibits activation of interferon regulatory factor 3

Stress granule formation induced by measles virus is protein kinase PKR dependent and impaired by RNA adenosine deaminase ADAR1

Measles virus nonstructural C protein modulates viral RNA polymerase activity by interacting with host protein SHCBP1

Influenza A virus inhibits cytoplasmic stress granule formation

Critical role of an antiviral stress granule containing RIG-I and PKR in viral detection and innate immunity

Binding of the influenza virus NS1 protein to double-stranded RNA inhibits the activation of the protein kinase that phosphorylates the elF-2 translation initiation factor

Japanese encephalitis virus core protein inhibits stress granule formation through an interaction with Caprin-1 and facilitates viral propagation

Sendai virus C protein plays a role in restricting PKR activation by limiting the generation of intracellular double-stranded RNA

Sendai virus trailer RNA binds TIAR, a cellular protein involved in virus-induced apoptosis

Rotavirus infection induces the phosphorylation of eIF2alpha but prevents the formation of stress granules

Interaction of TIA-1/TIAR with West Nile and dengue virus products in infected cells interferes with stress granule formation and processing body assembly

DHX36 enhances RIG-I signaling by facilitating PKR-mediated antiviral stress granule formation

MDA5 localizes to stress granules, but this localization is not required for the induction of type I interferon

Viral infection switches non-plasmacytoid dendritic cells into high interferon producers

PKR's protective role in viral myocarditis

West Nile virus-induced interferon production is mediated by the double-stranded RNAdependent protein kinase PKR

Protein kinase R contributes to immunity against specific viruses by regulating interferon mRNA integrity

The RNA-activated protein kinase enhances the induction of interferon-beta and apoptosis mediated by cytoplasmic RNA sensors

Selective contribution of IFN-alpha/beta signaling to the maturation of dendritic cells induced by doublestranded RNA or viral infection

IRF3 and IRF7 phosphorylation in virusinfected cells does not require double-stranded RNA-dependent protein kinase R or Ikappa B kinase but is blocked by Vaccinia virus E3L protein

Replication-dependent potent IFN-alpha induction in human plasmacytoid dendritic cells by a single-stranded RNA virus

C and V proteins of Sendai virus target signaling pathways leading to IRF-3 activation for the negative regulation of interferon-beta production

Stress granules and processing bodies are dynamically linked sites of mRNP remodeling

The dependence of viral RNA replication on co-opted host factors

Virus-host interactomes and global models of virus-infected cells

New insights into the role of RNase L in innate immunity

Small self-RNA generated by RNase L amplifies antiviral innate immunity

A distinct role of Riplet-mediated K63-Linked polyubiquitination of the RIG-I repressor domain in human antiviral innate immune responses

Pivotal role of RNA-binding E3 ubiquitin ligase MEX3C in RIG-I-mediated antiviral innate immunity

Stable formation of compositionally unique stress granules in virus-infected cells

Cytoplasmic heat shock granules are formed from precursor particles and are associated with a specific set of mRNAs

The dynamic state of heat shock proteins in chicken embryo fibroblasts

Stressful initiations

P bodies and the control of mRNA translation and degradation

P bodies: at the crossroads of posttranscriptional pathways

Mammalian stress granules and processing bodies

RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2 alpha to the assembly of mammalian stress granules

The RasGAP-associated endoribonuclease G3BP assembles stress granules

Stress granule assembly is mediated by prionlike aggregation of TIA-1

Tudor-SN and ADAR1 are components of cytoplasmic stress granules

Distinct structural features of caprin-1 mediate its interaction with G3BP-1 and its induction of phosphorylation of eukaryotic translation initiation factor 2alpha, entry to cytoplasmic stress granules, and selective interaction with a subset of mRNAs

Mammalian stress granules represent sites of accumulation of stalled translation initiation complexes

The deacetylase HDAC6 is a novel critical component of stress granules involved in the stress response

HuR binding to cytoplasmic mRNA is perturbed by heat shock

OGFOD1, a novel modulator of eukaryotic translation initiation factor 2alpha phosphorylation and the cellular response to stress

Ribonomic analysis of human Pum1 reveals cis-trans conservation across species despite evolution of diverse mRNA target sets

Dendritic localization of the translational repressor Pumilio 2 and its contribution to dendritic stress granules

Recruitment of the RNA helicase RHAU to stress granules via a unique RNA-binding domain

Rpp20 interacts with SMN and is redistributed into SMN granules in response to stress

Survival motor neuron protein facilitates assembly of stress granules

Staufen recruitment into stress granules does not affect early mRNA transport in oligodendrocytes

ZBP1 subcellular localization and association with stress granules is controlled by its Z-DNA binding domains

A role for eIF4E and eIF4E-transporter in targeting mRNPs to mammalian processing bodies

Cytoplasmic foci are sites of mRNA decay in human cells

The human LSm1-7 proteins colocalize with the mRNA-degrading enzymes Dcp1/2 and Xrnl in distinct cytoplasmic foci

Ge-1 is a central component of the mammalian cytoplasmic mRNA processing body

Multiple processing body factors and the ARE binding protein TTP activate mRNA decapping

A phosphorylated cytoplasmic autoantigen, GW182, associates with a unique population of human mRNAs within novel cytoplasmic speckles

The GW182 protein colocalizes with mRNA degradation associated proteins hDcp1 and hLSm4 in cytoplasmic GW bodies

Decapping and decay of messenger RNA occur in cytoplasmic processing bodies

Human retroviral host restriction factors APOBEC3G and APOBEC3F localize to mRNA processing bodies

Antiviral protein APOBEC3G localizes to ribonucleoprotein complexes found in P bodies and stress granules

Quantitative analysis of Argonaute protein reveals microRNA-dependent localization to stress granules

Argonaute 2/RISC resides in sites of mammalian mRNA decay known as cytoplasmic bodies

The translational regulator CPEB1 provides a link between dcp1 bodies and stress granules

The DEAD-box RNA helicase DDX3 associates with export messenger ribonucleoproteins as well as tip-associated protein and participates in translational control

Determination of the role of DDX3 a factor involved in mammalian RNAi pathway using an shRNA-expression library

Cellular microRNA and P bodies modulate host-HIV-1 interactions

RNA-associated protein 55 (RAP55) localizes to mRNA processing bodies and stress granules

The dsRNA protein kinase PKR: virus and cell control

PKR; a sentinel kinase for cellular stress

Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control

Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase

Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha

Uncharged tRNA activates GCN2 by displacing the protein kinase moiety from a bipartite tRNA-binding domain

Heme-regulated inhibitor kinase-mediated phosphorylation of eukaryotic translation initiation factor 2 inhibits translation, induces stress granule formation, and mediates survival upon arsenite exposure

Regulation of protein synthesis by heme-regulated eIF-2 alpha kinase

Analysis of subcellular G3BP redistribution during rubella virus infection

Cell proteins TIA-1 and TIAR interact with the 3 0 stem-loop of the West Nile virus complementary minus-strand RNA and facilitate virus replication

Modulation of hepatitis C virus RNA abundance and virus release by dispersion of processing bodies and enrichment of stress granules

Hepatitis C virus hijacks P-body and stress granule components around lipid droplets

The polypyrimidine tract-binding protein affects coronavirus RNA accumulation levels and relocalizes viral RNAs to novel cytoplasmic domains different from replication-transcription sites

Mouse hepatitis coronavirus replication induces host translational shutoff and mRNA decay, with concomitant formation of stress granules and processing bodies

Induction of stress granule-like structures in vesicular stomatitis virus-infected cells

Respiratory syncytial virus induces host RNA stress granules to facilitate viral replication

Activation of protein kinase R is required for induction of stress granules by respiratory syncytial virus but dispensable for viral replication

Roles of the respiratory syncytial virus trailer region: effects of mutations on genome production and stress granule formation

Arenavirus infection induces discrete cytosolic structures for RNA replication

Mammalian orthoreovirus escape from host translational shutoff correlates with stress granule disruption and is independent of eIF2alpha phosphorylation and PKR

Reovirus induces and benefits from an integrated cellular stress response

Formation of antiviral cytoplasmic granules during orthopoxvirus infection

Colocalization of transcription and translation within cytoplasmic poxvirus factories coordinates viral expression and subjugates host functions

Modulation of stress granules and P bodies during dicistrovirus infection

We were supported by the following grants: the Ministry of Education, Culture, Sports