PDF(Pubmed)
Abstract：
SARS-CoV-2 is a highly transmissible virus that causes COVID-19 disease. Mechanisms of viral pathogenesis include excessive inflammation and viral-induced cell death, resulting in tissue damage. We identified the host E3-ubiquitin ligase TRIM7 as an inhibitor of apoptosis and SARS-CoV-2 replication via ubiquitination of the viral membrane (M) protein. Trim7 -/- mice exhibited increased pathology and virus titers associated with epithelial apoptosis and dysregulated immune responses. Mechanistically, TRIM7 ubiquitinates M on K14, which protects cells from cell death. Longitudinal SARS-CoV-2 sequence analysis from infected patients revealed that mutations on M-K14 appeared in circulating variants during the pandemic. The relevance of these mutations was tested in a mouse model. A recombinant M-K14/K15R virus showed reduced viral replication, consistent with the role of K15 in virus assembly, and increased levels of apoptosis associated with the loss of ubiquitination on K14. TRIM7 antiviral activity requires caspase-6 inhibition, linking apoptosis with viral replication and pathology.
摘要：
SARS-CoV-2是一种高度传染性的病毒，可导致COVID-19疾病。病毒发病机制包括过度炎症和病毒诱导的细胞死亡，导致组织损伤.我们通过病毒膜（M）蛋白的泛素化鉴定了宿主E3-泛素连接酶TRIM7作为凋亡和SARS-CoV-2复制的抑制剂。Trim7-/-小鼠表现出与上皮凋亡和失调的免疫应答相关的病理学和病毒滴度增加。机械上,TRIM7泛素化K14上的M，保护细胞免受细胞死亡。感染患者的SARS-CoV-2纵向序列分析显示，在大流行期间，M-K14上的突变出现在循环变体中。在小鼠模型中测试这些突变的相关性。重组M-K14/K15R病毒显示病毒复制减少,与K15在病毒组装中的作用一致，以及与K14上泛素化丧失相关的凋亡水平增加。TRIM7抗病毒活性需要caspase-6抑制，将细胞凋亡与病毒复制和病理联系起来。
