期刊
SCIENCE ADVANCES
卷 4, 期 5, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aar2824
关键词
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资金
- National Natural Science Foundation of China [31522018, 91629101, 31601135, 81773058]
- National Key Basic Research Program of China [2015CB859800, 2014CB910800]
- Training Program for Outstanding Young Teachers in Higher Education Institutions of Guangdong Province [YQ2015001]
- CAMS Initiative for Innovative Medicine [CAMS-I2M, 2016-I2M-1-005]
- Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [2016ZX310194]
- Ministry of Science and Technology Project Grant [2014CB745203]
- Key Program for Innovative Drug Development of China [2015ZX09102023]
The innate immune response conferred by type I interferons is essential for host defense against viral infection but needs to be tightly controlled to avoid immunopathology. We performed a systematic functional screening by CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) knockout and overexpression to investigate the roles of the deubiquitinating enzyme (DUB) family in regulating antiviral immunity. We demonstrated that the expression of a large fraction of DUBs underwent complex temporal alteration, suggesting a dynamic program of feedback regulation. Moreover, we identified previously unrecognized roles of a subset of DUBs, including USP5, USP14, USP22, USP48, USP52, COPS5, and BRCC3, in inhibiting antiviral immunity at various levels. We explored an unexpected mechanism where multiple DUBs, such as USP5 and USP22, form diverse signalosomes with E3 ligases or DUBs to alter the substrates' ubiquitination state instead of directly cleaving the ubiquitin chains on substrates via their protease activity. Altogether, our study has revealed a panoramic view of the broad and dynamic involvement of DUB family proteins in regulating antiviral responses.
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