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Arms Race between Enveloped Viruses and the Host ERAD Machinery

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus

(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).
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viruses-08-00255-f001: (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).

Mentions: N-linked glycosylation starts from the membrane of the endoplasmic reticulum (ER), where the tetradecasaccharide precursor is assembled. This precursor consists of two N-acetylglucosamine (GlcNAc), nine mannose (Man, 4 are α1,2-linked), and three terminal glucose (Glc) residues distributed on three extended Man branches: a, b, and c (Glc3Man9GlcNAc2) (Figure 1A) [19,20]. When nascent polypeptides enter the ER lumen, the precursor is en bloc attached to Asn residues of a nascent polypeptide in a consensus Asn-X-(Ser/Thr) motif. After the attachment, these precursors are processed by a series of enzymes in both the ER and the Golgi apparatus to remold the core oligosaccharide into diverse N-linked glycan structures (Figure 1B). The first step in this process is the sequential removal of the two outermost Glc residues on branch A. The first Glc residue is removed by glucosidase I (GI), resulting in the di-glycosylated oligosaccharide Glc2Man9GlcNAc2, which is recognized by an ER transmembrane lectin malectin [21]. The second Glc residue is then removed by glucosidase II (GII), resulting in the mono-glucosylated oligosaccharide Glc1Man9GlcNAc2, which is recognized by two other ER lectins, the membrane-bound calnexin (CNX) and/or soluble calreticulin (CRT). Interaction with these two chaperones segregates the newly formed glycoprotein and provides access to protein disulfide isomerases (PDIs) such as ERp57, which promotes disulfide bond formation, resulting in protein folding into a native conformation. Once a protein is properly folded, GII cleaves the last Glc residue on branch A, which releases the protein from the CNX/CRT cycle. The ER class I α-mannosidase (ERManI) then cleaves the outermost Man residue on branch b on native proteins, resulting in the oligosaccharide Man8GlcNAc2. These high-Man glycans are then recognized by lectins including ER-Golgi intermediate compartment-53 (ERGIC-53), vesicular integral membrane protein of 36Kda (VIP36), and VIP36-like (VIPL), which promote trafficking from the ER to the Golgi [22]. The remaining Man residues are cleaved by the Golgi mannosidases, and the glycan remolding process is continued through the remainder of the N-glycosylation pathway, which generates functional glycoproteins that are delivered to the cell surface (Figure 1B).


Arms Race between Enveloped Viruses and the Host ERAD Machinery
(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).
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Related In: Results  -  Collection

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viruses-08-00255-f001: (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).
Mentions: N-linked glycosylation starts from the membrane of the endoplasmic reticulum (ER), where the tetradecasaccharide precursor is assembled. This precursor consists of two N-acetylglucosamine (GlcNAc), nine mannose (Man, 4 are α1,2-linked), and three terminal glucose (Glc) residues distributed on three extended Man branches: a, b, and c (Glc3Man9GlcNAc2) (Figure 1A) [19,20]. When nascent polypeptides enter the ER lumen, the precursor is en bloc attached to Asn residues of a nascent polypeptide in a consensus Asn-X-(Ser/Thr) motif. After the attachment, these precursors are processed by a series of enzymes in both the ER and the Golgi apparatus to remold the core oligosaccharide into diverse N-linked glycan structures (Figure 1B). The first step in this process is the sequential removal of the two outermost Glc residues on branch A. The first Glc residue is removed by glucosidase I (GI), resulting in the di-glycosylated oligosaccharide Glc2Man9GlcNAc2, which is recognized by an ER transmembrane lectin malectin [21]. The second Glc residue is then removed by glucosidase II (GII), resulting in the mono-glucosylated oligosaccharide Glc1Man9GlcNAc2, which is recognized by two other ER lectins, the membrane-bound calnexin (CNX) and/or soluble calreticulin (CRT). Interaction with these two chaperones segregates the newly formed glycoprotein and provides access to protein disulfide isomerases (PDIs) such as ERp57, which promotes disulfide bond formation, resulting in protein folding into a native conformation. Once a protein is properly folded, GII cleaves the last Glc residue on branch A, which releases the protein from the CNX/CRT cycle. The ER class I α-mannosidase (ERManI) then cleaves the outermost Man residue on branch b on native proteins, resulting in the oligosaccharide Man8GlcNAc2. These high-Man glycans are then recognized by lectins including ER-Golgi intermediate compartment-53 (ERGIC-53), vesicular integral membrane protein of 36Kda (VIP36), and VIP36-like (VIPL), which promote trafficking from the ER to the Golgi [22]. The remaining Man residues are cleaved by the Golgi mannosidases, and the glycan remolding process is continued through the remainder of the N-glycosylation pathway, which generates functional glycoproteins that are delivered to the cell surface (Figure 1B).

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus