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Review
. 2021 Dec 15;85(4):e0003521.
doi: 10.1128/MMBR.00035-21. Epub 2021 Oct 13.

Endoplasmic Reticulum Chaperones in Viral Infection: Therapeutic Perspectives

Evelyne Kohli  1   2 , Sébastien Causse  1 , Valentin Baverel  1 , Laurence Dubrez  1 , Natalia Borges-Bonan  1 , Oleg Demidov  1   3 , Carmen Garrido  1   4
Affiliations
Review

Endoplasmic Reticulum Chaperones in Viral Infection: Therapeutic Perspectives

Evelyne Kohli et al. Microbiol Mol Biol Rev. .

Abstract

Viruses are intracellular parasites that subvert the functions of their host cells to accomplish their infection cycle. The endoplasmic reticulum (ER)-residing chaperone proteins are central for the achievement of different steps of the viral cycle, from entry and replication to assembly and exit. The most abundant ER chaperones are GRP78 (78-kDa glucose-regulated protein), GRP94 (94-kDa glucose-regulated protein), the carbohydrate or lectin-like chaperones calnexin (CNX) and calreticulin (CRT), the protein disulfide isomerases (PDIs), and the DNAJ chaperones. This review will focus on the pleiotropic roles of ER chaperones during viral infection. We will cover their essential role in the folding and quality control of viral proteins, notably viral glycoproteins which play a major role in host cell infection. We will also describe how viruses co-opt ER chaperones at various steps of their infectious cycle but also in order to evade immune responses and avoid apoptosis. Finally, we will discuss the different molecules targeting these chaperones and the perspectives in the development of broad-spectrum antiviral drugs.

Keywords: DNAJ; ER chaperone; GRP78; GRP94; calnexin; calreticulin; protein disulfide isomerase; viral infection.

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Figures

FIG 1
FIG 1
Glucose-regulated ER chaperone structures. (A) GRP78. Upper panel, structure in the ATP-bound state (SMTL ID 5e84). NBD, nucleotide binding domain; SBD, substrate binding domain. Arrows indicate the two sites which have been targeted by inhibitors, i.e., the ATP binding site for ATPase inhibitors (ATP mimicry) and the site of interaction (SBDβ) with the glycoprotein S of SARS-CoV-2 (205). Lower panel, GRP78 folding cycle. Involvement of cochaperones (DNAJ, NEF) and inhibitors are shown. (B) GRP94. Upper panel, structure in the ATP-bound state (homodimer, SMTL ID 5uls.1). PU-WS13 targets the ATP binding site (109). Lower panel, GRP94 cycle. Exactly where in the cycle the client proteins are bound and released is unclear.
FIG 2
FIG 2
Summary of the role of ER chaperones in viral entry of enveloped (A) and nonenveloped (B) viruses. (A) Enveloped viruses. ER chaperones involved either in viral attachment as coreceptors or through specific client proteins or in fusion. (B) Nonenveloped viruses, for example, polyomaviruses. PDIs, GRP78, and DNAJ ER chaperones work in conjunction with cytosolic chaperones to allow cytosolic entry of polyomaviruses after trafficking to the ER following receptor-mediated endocytosis. Inside the ER, PDIs first destabilize the capsid, exposing the hydrophobic VP2 and VP3 proteins. This allows GRP78 binding and transport to the ER membrane, where the capsid binds to the B cell receptor-associated protein 31 (BAP31) and is inserted. Various transmembrane DNAJs contribute to forming foci at the membrane, where the inserted capsids are extracted into the cytosol by HSC70 and HSP105.
FIG 3
FIG 3
Summary of the roles of ER chaperones in viral protein folding, virus assembly, RNA replication, and cell exit. (A) Viral protein folding. ER chaperones reported to interact with, fold, or degrade the listed viral proteins. FLUAV, influenza A virus; RABV, rabies virus; RV, rotavirus. (B) Virus assembly. GRP78 contributes to the structure and function of the viral assembly compartment (VAC) of CMV. (C) RNA replication. ER chaperones involved in replication factories of flaviviruses. (D) Cell exit. GRP78 is involved in EBOV cell exit.
FIG 4
FIG 4
CNX/CRT and PDI cycles. (A) CNX/CRT cycle. N-linked glycoproteins are cotranslationally modified at the luminal face of the ER through the addition of one or more precursor glycans in the form of Glc3Man9GlcNAc2 by the oligosaccharyl transferase complex (OST). Interaction of the nascent polypeptide chain with CNX/CRT takes place after sequential cleavage of the two terminal glucose residues by glucosidases I and II. Folded glycoproteins are transported to the Golgi compartment following release of the third and last terminal glucose by glucosidase II. If a protein is misfolded, it is reglucosylated by UDP-glucose:glycoprotein glucosyltransferase (UGGT) to allow its rebinding to CNX/CRT. This is referred to as the CNX/CRT folding cycle. Proteins that fail to emerge from the CNX/CRT folding cycle in a folded state are targeted for ERAD. The inhibitors so far described of the CNX/CRT cycle target glucosidases I and II. (B) PDI cycle. Oxidized PDIs catalyze disulfide bond formation of nascent peptides in the ER (upper part). At the cell membrane, PDIs act primarily as reductants of viral glycoproteins and induce conformational changes allowing fusion (lower part). Arrows indicate the sites which have been targeted by inhibitors.
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