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Review
. 2016 Jul;14(7):407-420.
doi: 10.1038/nrmicro.2016.60. Epub 2016 Jun 6.

Opportunistic intruders: how viruses orchestrate ER functions to infect cells

Madhu Sudhan Ravindran #  1 , Parikshit Bagchi #  1 , Corey Nathaniel Cunningham  1 , Billy Tsai  1
Affiliations
Review

Opportunistic intruders: how viruses orchestrate ER functions to infect cells

Madhu Sudhan Ravindran et al. Nat Rev Microbiol. 2016 Jul.

Abstract

Viruses subvert the functions of their host cells to replicate and form new viral progeny. The endoplasmic reticulum (ER) has been identified as a central organelle that governs the intracellular interplay between viruses and hosts. In this Review, we analyse how viruses from vastly different families converge on this unique intracellular organelle during infection, co-opting some of the endogenous functions of the ER to promote distinct steps of the viral life cycle from entry and replication to assembly and egress. The ER can act as the common denominator during infection for diverse virus families, thereby providing a shared principle that underlies the apparent complexity of relationships between viruses and host cells. As a plethora of information illuminating the molecular and cellular basis of virus-ER interactions has become available, these insights may lead to the development of crucial therapeutic agents.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Endogenous functions of the ER.
a | Protein biosynthesis. The endoplasmic reticulum (ER) is the site for the biosynthesis of membrane and luminal proteins that function in the ER and in the classical secretory pathway, as well as for the biosynthesis of secreted proteins. In this process, a nascent polypeptide client is co-translationally translocated through the SEC61 translocon into the lumen of the ER (for luminal proteins) or laterally into the ER bilayer (for membrane proteins). The client protein then undergoes post-translational modifications to assist in its folding and assembly — tasks that are carried out by dedicated ER-localized enzymes or chaperones (oligosaccharyl transferase (OST), protein disulfide isomerase (PDI) family members and binding immunoglobulin protein (BiP)). b | Protein secretion. After folding and assembly, the client is packaged into a coat protein complex II (COPII)-coated vesicle that buds out of the ER. The client protein is transported through the classical secretory pathway en route to other cellular destinations or to the cell surface for secretion. c | Unfolded protein response (UPR). When a client protein misfolds or misassembles, it triggers the UPR, which stimulates a stress signalling cascade (through the activation of ER membrane sensors) that is intended to rectify the misfolding of proteins. d | ER-associated degradation (ERAD). Despite this effort to rectify protein misfolding, if the client remains terminally misfolded, it is then subjected to degradation by a process known as ERAD. During ERAD, a misfolded substrate is processed and retro-translocated into the cytosol for proteasome-mediated degradation. e | Calcium homeostasis. The ER also stores Ca2+ and controls its homeostasis — a process that is regulated by different calcium channels and pumps in the ER membrane that directly communicate with calcium channels in the plasma membrane. f | Lipid biogenesis. The ER is also the centre for lipid biogenesis, in which different lipid biosynthetic enzymes that are embedded and/or associated with the ER membrane generate lipids (sphingolipids, phospholipids and sterols) that are used for structural or signalling purposes. SH, sulfhydryl group. PowerPoint slide
None
SH, sulfhydryl group.
Figure 2
Figure 2. Exploiting the ER during the early stages of infection.
a | Entry-associated disassembly. Viruses must disassemble their capsid to release their genome. Members of the Polyomaviridae disassemble their capsid by co-opting components of the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. To cause infection, polyomaviruses undergo receptor-mediated endocytosis and traffic to the ER (step 1). Once at the ER, they use protein disulfide isomerase (PDI)-family members to isomerize and reduce viral disulfide bonds (step 2). These events partially disassemble the virus particles to form hydrophobic viruses that engage binding immunoglobulin protein (BiP) through the activity of ER DNAJ domain-containing protein 3 (ERDJ3; step 3). 170 kDa glucose-regulated protein (GRP170) then releases polyomavirus from BiP, enabling the hydrophobic virus to insert into the ER membrane (step 4). The membrane-inserted virus reorganizes selective ER membrane proteins (B cell receptor-associated protein 31 (BAP31) and the J proteins DNAJ homologue subfamily B member 12 (DNAJB12), DNAJB14 and DNAJ C18) in the lipid bilayer to form foci (step 5). The membrane-attached cytosolic extraction machinery (heat shock cognate protein 70 (HSC70)–heat shock protein 105 (HSP105)–small glutamine-rich tetratricopeptide repeat-containing protein-α (SGTA)) then ejects the virus from the foci into the cytosol in a reaction that simultaneously disassembles the virus (step 6). Cytosolic disassembly enables the resulting core virus particle to move into the nucleus to cause infection. b | Genome translation. Some viruses exploit the ER-associated biosynthetic machinery to translate their genetic code in two ways: the translation of viral structural proteins that are incorporated into virions (for example, the envelope glycoprotein of HIV and haemagglutinin of influenza A virus (IAV)) and the translation of viral non-structural proteins that promote the subsequent viral replication step. This is evident during translation of the positive-sense RNA ((+)RNA) genome of viruses in the Flaviviridae (hepatitis C virus (HCV), dengue virus (DENV) and West Nile virus WNV) and Coronaviridae (severe acute respiratory syndrome coronavirus (SARS-CoV)) families, in which the newly synthesized replication proteins target to sites of virus replication on the ER (or ER-derived) membrane compartments in preparation for replication. At these sites, the physical architecture of the ER membrane effectively acts as a scaffold to recruit the viral replication proteins. PowerPoint slide
Figure 3
Figure 3. Co-opting the ER to promote the later stages of infection.
Viruses can co-opt functions that are associated with the endoplasmic reticulum (ER) to achieve the four crucial later steps in infection — replication, assembly, morphogenesis and egress. a | Genome replication. During this process, the replication proteins of numerous viruses rearrange the ER membrane to generate membranous structures with different morphologies and terminologies, such as invaginated vesicles (for dengue virus (DENV) and West Nile virus (WNV)) and double-membrane vesicles (DMVs; for hepatitis C virus (HCV), poliovirus and enterovirus 71 (EV71)). These replication sites act to increase the local concentrations of viral and host components that are essential for RNA replication, and enable different steps of the replication process to be coordinated efficiently. b | Assembly. Virus assembly can be tightly coupled to, and coordinated with, genome replication, as exemplified in HCV. To initiate the assembly of viral progeny, a lipid droplet recruits viral core proteins to its surface and delivers them to the site of assembly. In one model of HCV virion assembly, core proteins capture the newly replicated positive-sense RNA ((+)RNA) that extrudes from the neighbouring DMV, forming the nucleocapsid. The nucleocapsid may then bud into the lumen of the ER, generating a newly assembled enveloped virus particle that contains the structural glycoproteins E1 and E2. c | Morphogenesis. Morphogenesis of the assembled HCV particle continues in the ER, with the acquisition of lipoproteins on its surface to generate the mature 'lipoviral' HCV particle that is poised to exit the host cell. For rotavirus, ER-dependent morphogenesis is initiated when its membrane protein non-structural protein 4 (NSP4) induces calcium release from the ER. This triggers a signalling cascade that delivers the structural proteins VP4 and VP7, with assistance from NSP4, to the ER membrane assembly site. The VP4–NSP4–VP7 complex recruits the double-layer particle (DLP) and deforms the membrane to form a transient enveloped intermediate in the lumen of the ER. Following the removal of the ER-derived lipid bilayer, VP7 correctly assembles on the surface of the mature infectious triple-layer particle (TLP), with the simultaneous release of NSP4. The morphologically matured virion then exits the host cell through lysis or secretion. d | Egress. The final step of infection is egress of the mature virion. Viruses that mature in the ER co-opt the ER-dependent secretory pathway to access the extracellular milieu. Examples of using this strategy can be found in egress of the mature HCV, rotavirus and parvovirus particles. Additionally, the ER could also have specific components, such as the KDEL receptor in the case of DENV, that are hijacked to promote exit. COPII, coat protein complex II. PowerPoint slide
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