Endoplasmic reticulum-associated degradation controls virus protein homeostasis that is required for the flavivirus propagation.

Tabata, Keisuke; Arakawa, Masashi; Ishida, Kotaro; Kobayashi, Makiko; Nara, Atsuki; Sugimoto, Takehiro; Okada, Tetsuya; Mori, Kazutoshi; Morita, Eiji

Many positive-stranded RNA viruses encode polyproteins and viral proteins are generated by processing the polyproteins. This system produces an equal amount of each viral protein, though their required amounts are different. In this study, we found that the extra membrane-anchored non-structural (NS) proteins of Japanese encephalitis virus and dengue virus are rapidly and selectively degraded by the endoplasmic reticulum-associated degradation (ERAD) pathway. Our gene targeting study revealed that ERAD involving Derlin2 and SEL1L, but not Derlin1, is required for the viral genome replication. Derlin2 predominantly localized in the convoluted membrane (CM) of viral replication organelle, and viral NS proteins degraded in the CM. Hence, these results suggest that viral protein homeostasis is regulated by Derlin2-mediated ERAD in the CM, and this process is critical for the propagation of these viruses.ImportanceThe results of this study reveal that the cellular ERAD system controls the amount of each viral protein in virus-infected cells; this "viral protein homeostasis" is critical for viral propagation. Furthermore, we clarified that the "convoluted membrane (CM)," which was previously considered a structure with unknown function, serves as a kind of waste dump where viral protein degradation occurs. We also found that the Derlin2/Sel1L/HRD1-specific pathway is involved in this process, whereas the Derlin1-mediated pathway is not. This novel ERAD-mediated fine-tuning system for the stoichiometries of polyprotein-derived viral proteins may represent a common feature among polyprotein-encoding viruses.