Arms Race between Enveloped Viruses and the Host ERAD Machinery

Abstract

Enveloped viruses represent a significant category of pathogens that cause serious diseases in animals. These viruses express envelope glycoproteins that are singularly important during the infection of host cells by mediating fusion between the viral envelope and host cell membranes. Despite low homology at protein levels, three classes of viral fusion proteins have, as of yet, been identified based on structural similarities. Their incorporation into viral particles is dependent upon their proper sub-cellular localization after being expressed and folded properly in the endoplasmic reticulum (ER). However, viral protein expression can cause stress in the ER, and host cells respond to alleviate the ER stress in the form of the unfolded protein response (UPR); the effects of which have been observed to potentiate or inhibit viral infection. One important arm of UPR is to elevate the capacity of the ER-associated protein degradation (ERAD) pathway, which is comprised of host quality control machinery that ensures proper protein folding. In this review, we provide relevant details regarding viral envelope glycoproteins, UPR, ERAD, and their interactions in host cells.

Keywords: ER stress; ERAD; UPR; endoplasmic reticulum-associated degradation; enveloped viruses; unfolded protein response; viral glycoproteins.

Figure 1

(A) Schematic presentation of the N-linked core oligosaccharide structure. The core is composed of two N-acetylglucosamine (GlcNAc, blue), nine mannose (Man, red), and three glucose (Glc, yellow) residues. a, b, and c are three oligosaccharide branches. (B) Schematic description of N-glycosylation, endoplasmic reticulum-associated protein degradation (ERAD), and endoplasmic reticulum (ER) stress pathways. Nascent polypeptides are translocated through Sec61 into the rough ER, where the core oligosaccharide is transferred from a dolichol phosphate onto asparagine residues in asparagine-X-serine/threonine (NXS/T) motifs (I). The two terminal glucose residues on the core oligosaccharide are trimmed by glucosidase I, (GI) (II), and GII (III), respectively, allowing for the association with the chaperones, membrane-bound calnexin (CNX) and and/or soluble calreticulin (CRT), which promote folding to a native conformation. Eventually, the last terminal glucose residue will be trimmed by GII, and the glycoprotein will attain a native conformation (IV), or misfold (VII). Glycoproteins that reach a native conformation will have the terminal α1,2-Man residue on the b branch removed by ER class I α-mannosidase (ERManI) (V), as a signal to allow it to traverse the canonical secretory pathway for surface presentation or secretion (VI). Polypeptides unable to reach a native conformation (VII) will engage in multiple rounds of the CNX/CRT cycle, facilitated by reglucosylation of the terminal glucose by UDP-Glc:unfolded glycoprotein glucosyltransferase (UGGT) (VIII), and trafficking between quality control vesicles (QCV) (IX) and the the ER-derived quality compartments (ERQC) (X) under ER stress. Terminally misfolded glycoproteins will be demannosylated to remove all α1,2-Man residues (XI), followed by association with lectins osteosarcoma amplified 9 (OS9) and XTP3-transactivated gene B protein (XTP3-B) for ERAD (XII). ERManI containing QCV are rapidly recycled through autophagy/lysosome pathways (XIII). Without interactions with client glycoproteins, EDEMosome components are degraded through an autophagy-like mechanism (XIV). Viruses can hijack EDEMosomes to form double membrane vesicles (DMVs) that serve as platforms for their replication (XV).