期刊
SCIENCE ADVANCES
卷 7, 期 2, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abd9732
关键词
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资金
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDB29010205]
- National Natural Science Foundation of China [31670172, 31930016, 31670169, 31770189]
- Beijing Municipal Science and Technology Commission [Z181100001318009]
- Beijing Advanced Innovation Center for Genomics at Peking University
- Peking-Tsinghua Center for Life Sciences
- West Light Foundation of the Chinese Academy of Sciences [xbzg-zdsys-201909]
- Natural Science Foundation of Guangdong Province [2019A1515110668]
Through a genome-wide CRISPR-Cas9 screening, the study identified E3 ligase TRIM26 as a critical host factor for HCV replication, with its deficiency impairing HCV genome replication. Mechanistic studies revealed that TRIM26 mediates the ubiquitination of HCV-encoded NS5B protein and promotes HCV genome replication, while the unique structure of mouse TRIM26 prevents its support for HCV replication, unlike human TRIM26 which can promote HCV infection.
Hepatitis C virus (HCV) remains a major human pathogen that requires better understanding of virus-host interactions. In this study, we performed a genome-wide CRISPR-Cas9 screening and identified TRIM26, an E3 ligase, as a critical HCV host factor. Deficiency of TRIM26 specifically impairs HCV genome replication. Mechanistic studies showed that TRIM26 interacts with HCV-encoded NS5B protein and mediates its K27-linked ubiquitination at residue K51, and thus promotes the NS5B-NS5A interaction. Moreover, mouse TRIM26 does not support HCV replication because of its unique six-amino acid insert that prevents its interaction with NS5B. Ectopic expression of human TRIM26 in a mouse hepatoma cell line that has been reconstituted with other essential HCV host factors promotes HCV infection. In conclusion, we identified TRIM26 as a host factor for HCV replication and a new determinant of host tropism.These results shed light on HCV-host interactions and may facilitate the development of an HCV animal model.
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