title: Role of the endoplasmic reticulum-associated degradation (ERAD) pathway in degradation of hepatitis C virus envelope proteins and production of virus particles.
abstract: Viral infections frequently cause endoplasmic reticulum (ER) stress in host cells leading to stimulation of the ER-associated degradation (ERAD) pathway, which subsequently targets unassembled glycoproteins for ubiquitylation and proteasomal degradation. However, the role of the ERAD pathway in the viral life cycle is poorly defined. In this paper, we demonstrate that hepatitis C virus (HCV) infection activates the ERAD pathway, which in turn controls the fate of viral glycoproteins and modulates virus production. ERAD proteins, such as EDEM1 and EDEM3, were found to increase ubiquitylation of HCV envelope proteins via direct physical interaction. Knocking down of EDEM1 and EDEM3 increased the half-life of HCV E2, as well as virus production, whereas exogenous expression of these proteins reduced the production of infectious virus particles. Further investigation revealed that only EDEM1 and EDEM3 bind with SEL1L, an ER membrane adaptor protein involved in translocation of ERAD substrates from the ER to the cytoplasm. When HCV-infected cells were treated with kifunensine, a potent inhibitor of the ERAD pathway, the half-life of HCV E2 increased and so did virus production. Kifunensine inhibited the binding of EDEM1 and EDEM3 with SEL1L, thus blocking the ubiquitylation of HCV E2 protein. Chemical inhibition of the ERAD pathway neither affected production of the Japanese encephalitis virus (JEV) nor stability of the JEV envelope protein. A co-immunoprecipitation assay showed that EDEM orthologs do not bind with JEV envelope protein. These findings highlight the crucial role of the ERAD pathway in the life cycle of specific viruses.
authors: Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
authors: Mohsan
authors: M
authors: Saeed
authors: Ryosuke
authors: R
authors: Suzuki
authors: Noriyuki
authors: N
authors: Watanabe
authors: Takahiro
authors: T
authors: Masaki
authors: Mitsunori
authors: M
authors: Tomonaga
authors: Amir
authors: A
authors: Muhammad
authors: Takanobu
authors: T
authors: Kato
authors: Yoshiharu
authors: Y
authors: Matsuura
authors: Haruo
authors: H
authors: Watanabe
authors: Takaji
authors: T
authors: Wakita
authors: Tetsuro
authors: T
authors: Suzuki
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D060746:Endoplasmic Reticulum-Associated Degradation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism* / Q000821:virology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects / Q000235:genetics; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism*; D014771:Virion / Q000235:genetics / Q000378:metabolism*
chemical_list: D000470:Alkaloids; C486654:EDEM1 protein, human; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D011506:Proteins; C117384:SEL1L protein, human; D014759:Viral Envelope Proteins; C065629:kifunensine