key: cord-0780327-qxbtusi6
authors: McEwan, William A.
title: Antibodies in the intracellular domain
date: 2022-02-28
journal: Semin Cell Dev Biol
DOI: 10.1016/j.semcdb.2022.02.020
sha: 76cc382d48c1b8d92832ad38d23fdafd0f640980
doc_id: 780327
cord_uid: qxbtusi6

nan

Antibodies in the intracellular domain Antibodies are one of the most useful discoveries in the biological sciences. They are applied in countless scientific and diagnostic procedures to label, image, purify and probe the molecular world. For many research labs the box of antibodies is therefore one of the most treasured and frequently-visited resources. The usefulness of antibodies to researchers mirrors their usefulness to the immune system: they can selectively bind to, and render visible, virtually any molecular pattern. Antibodies against SARS-CoV-2 in the bloodstream make viruses visible to leucocytes; antibodies in lateral flow devices make viruses visible to the eye. Over the past few decades, antibodies have found further usefulness in medicine. Five of the top ten drugs by sales are now antibodies or antibody derivatives. These immunotherapies have transformed modern medicine, particularly in cancers and immunological diseases where they improve the quality and length of countless lives.

Since their original description by Emil von Behring and Kitasato Shibasaburo in 1890, antibodies have been associated with the humours, the cell-free fluids of the body. They are secreted by B-cells into extracellular spaces and engage extracellular targets. All 100 FDAapproved antibody-based drugs engage proteins that are accessible to the humours: either secreted or membrane-associated proteins at or near the cell surface. Of the 12,813 proteins detailed so far by the Human Protein Atlas [1] , about one-third are secreted. Of the cell-associated remainder, only 15% are present at the plasma membrane. By comparison, 36% are expressed in the cytosol with an overlapping 48% residing in the nucleus. These intracellular proteins include many medically important targets including most signalling pathway components, almost all kinases, many pathogen-derived proteins, and several proteins related to neurodegenerative disease. The inability of antibodies to reach these intracellular targets is therefore a major constraint on the use of antibodies as therapies.

Recent work is revealing that antibodies can, in specific circumstances and limited quantities, gain access to the intracellular environment. Entry can be in complex with infectious agents including bacteria, viruses and prion-like proteins such as tau. In these cases, the translocation of antibodies to the cytosol is facilitated by the membranecrossing or membrane-disrupting properties of the target. In other cases, free antibodies are found to accumulate inside cells. Whether the entry of free antibodies is a rare event associated with specific antibody idiotypes and specific disease states, or whether there are mechanisms that enable antibody transfer to the cytosol, remains poorly defined. Regardless, where it can be achieved, the entry of antibodies to the intracellular domain has potentially powerful consequences. Intracellular antibodies can alter normal protein function and label proteins for rapid destruction. This latter area has gained mechanistic detail since the description of an intracellular antibody receptor, TRIM21. Here again, antibodies make their targets visible, in this context to the cell's waste-disposal machinery, stimulating a specific and rapid degradation response.

In this Special Edition, I have tried to bring a collection of authors together to document some of the major advances in this area. The reviews cover both the biological underpinning of antibodies in the intracellular domain and the new uses that antibodies in the intracellular environment are acquiring. This inevitably means the reviews are cross-disciplinary, with contributions originating from virology, cellular neurosciences, molecular imaging techniques, protein degradation and neurodegeneration. Kiss and James provide an overview of TRIM21 and the molecular mechanisms governing its activity against cytosolic immune complexes. Botterman and Caddy describe how antibodies act in the intracellular environment to limit virus replication, including detailing how antigen presentation can be promoted by cytosolic antibodies. Trimmer delineates new frontiers in the technological application of antibodies to visualise structures within neurons and modulate their cell biology. Congdon and Sigurdsson present the case that immunotherapy against tau in neurodegenerative disease should seek to promote intracellular effects. Finally, from my own group, Benn et al. detail recent advances in using intracellular antibodies to target proteins in neurodegenerative disease. By bringing together these ideas here my aim is to highlight the areas of progress and to expose where the main outstanding research questions reside. Our sincere hope is that antibodies will, in the coming years, find a new level of usefulness in the intracellular domain to rival their track record in the humours. 

Proteomics. Tissue-based map of the human proteome

Contents lists available at ScienceDirect Seminars in Cell and Developmental Biology journal homepage