Chapter Six - Endoplasmic reticulum in viral infection

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Abstract

Virus exploits host cellular machinery to replicate and form new viral progeny and endoplasmic reticulum (ER) plays central role in the interplay between virus and host cell. Here I will discuss how cellular functions of ER being utilized by viruses from different families during different stages of pathogenesis. Flow of knowledge related to this area of research based on interdisciplinary approach, using biochemical and cell biological assays coupled with advanced microscopy strategies, is pushing our understanding of the virus-ER interaction during infection to the next level.

Introduction

The Endoplasmic reticulum (ER) is a major cellular organelle with continuous membranous system consisting outer nuclear envelope and forms a network of tubules and sheets. Vast cellular functions of ER are the result of its very dynamic morphology (Schuldiner and Schwappach, 2013; Westrate et al., 2015). Rough ER is the site for active protein biosynthesis, whereas the smooth ER functions in lipid metabolism and harbors detoxifying enzymes (Shimizu and Hendershot, 2007; Voeltz et al., 2002). When a newly synthesized protein is translated and folded properly in the ER lumen by ER luminal chaperones, it exits the ER to reach the Golgi apparatus via membrane budding mediated by the COPII complex. But if a protein gets misfolded in the ER, an endogenous ER quality control system called ER-associated degradation (ERAD) relieves the build-up of misfolded ER proteins (Brodsky and Skach, 2011; Smith et al., 2011). To do so, a network of ER factors recognizes and retro-translocates the misfolded protein to the cytosol. On reaching the cytosol, another brigade of cytosolic factors engages and ubiquitinate the substrate, targeting it to the proteasome for degradation. Now, viruses use some of the ER's general property for their benefit. For example, as the ER-to-cytosol retro-translocation machinery related to mostly ERAD pathway is an inherent apparatus in the ER, it represents an ideal factor for certain viruses to enter the cytosol. Whereas, ER membrane's ability to undergo constant budding reactions plays a significant role during viral replication and assembly when viruses deform and rearrange the ER membrane to generate ER-derived structures used to support these processes. Diverse functions of ER made this organelle favorite for viruses. In this chapter, we will explore how viruses exploit almost all functions of ER to propagate inside host cell.

Section snippets

ER morphology

ER discovered by Emilio Veratti in the year of 1902 as Sarcoplasmic Reticulum in muscle fibers which is similar to ER in other cells (Veratti, 1961). Fifty years later, this new organelle was first visualized through electron microscopy (EM) by Keith Porter and termed it as “endoplasmic reticulum” (Porter, 1953). While nuclear envelope is one of the two domains of ER, other domain of ER, called peripheral ER contains sheets and tubules (Westrate et al., 2015) (Fig. 1), spread throughout the

Co-opting ER localized protein synthesis machinery by viruses

After entry into host cell, viruses (both DNA and RNA) disassembled and expose their genetic material which needs to be transcribed and/or translated depending on the nature of the genome. Translation of viral genetic material first generates viral structural proteins which are necessary for virion production, second produces viral non-structural proteins that prepare and promote the ensuing replication of the viral genome.

Viruses like HIV-1, Influenza A virus (IAV), Hepatitis E virus (HEV) and

Conclusions and future perspectives

Viruses utilize host cellular machinery for their replication and pathogenesis. As ER plays central role in maintaining cellular homeostasis and modulates vast arrays of cellular functions, it is one the most favored organelle for viruses to exploit. Almost every functions of ER are targeted by different viruses during various stages of infection. While polyomavirus utilize ER during early stages of infection, some other viruses like flavivirus, HCV, poliovirus exploit ER during both early and

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