Crystal Structure of the C-Terminal Cytoplasmic Domain of Non-Structural Protein 4 from Mouse Hepatitis Virus A59

Xu, Xiaoling; Lou, Zhiyong; Ma, Yanlin; Chen, Xuehui; Yang, Zhangsheng; Tong, Xiaohang; Zhao, Qi; Xu, Yuanyuan; Deng, Hongyu; Bartlam, Mark; Rao, Zihe

Association of RNA replication with the cytoplasmic membranes of infected cells is a typical feature of all characterized positive-strand RNA viruses to date [16, 17, 18, 19] . Van der Meer and colleagues demonstrated that MHV RNA synthesis and genome replication occur on late endosomal or lysosomal membranes [20] . In contrast, Gosert and coworkers reported that the MHV replication complex is localized to the cellular double membrane vesicles (DMVs); the RNA synthesis, replication and subgenomic mRNA transcription also take place in the cytoplasmic DMVs [21] . It was further demonstrated that the autophagic pathway is required for formation of virus induced double membrane vesicles, and formation of DMVs significantly enhances the efficiency of MHV replication [22] . An electron microscopy study also revealed the involvement of DMVs in formation of the SARS coronavirus replication complex; the DMVs were labeled by several nsps and viral RNA, and the endoplasmic reticulum (ER) was identified as the most likely membrane donor of SARS-CoV induced membrane structures [14] . Thus, it is generally believed that coronavirus replication takes places on the cytoplasmic DMVs, the membranes of which originate from the ER [23] . However, the mechanism of interaction between the replication complex and membranes are unclear and require further investigation.