期刊
SCIENTIFIC REPORTS
卷 5, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/srep11220
关键词
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资金
- National Natural Sciences Foundation of China [31490602, 31225027, 31421064]
- National Basic Research Program (973) of China [2014CB542700]
- Natural Science Foundation of Hubei Province [2014CFA009]
- Key grant Project of Chinese Ministry of Education [313025]
- Fundamental Research Funds for the Central Universities [2013PY043, 2013PY055]
Viral infection triggers a series of signaling cascades, which converge to activate the transcription factors nuclear factor-kappa B (NF-kappa B) and interferon regulatory factor 3 (IRF3), thereby inducing the transcription of type I interferons (IFNs). Although not fully characterized, these innate antiviral responses are fine-tuned by dynamic ubiquitination and deubiquitination processes. In this study, we report ubiquitin-specific protease (USP) 15 is involved in regulation of the retinoic acid-inducible gene I (RIG-I)-dependent type I IFN induction pathway. Knockdown of endogenous USP15 augmented cellular antiviral responses. Overexpression of USP15 inhibited the transcription of IFN-beta. Further analyses identified histidine 862 as a critical residue for USP15's catalytic activity. Interestingly, USP15 specifically removed lysine 63-linked polyubiquitin chains from RIG-I among the essential components in RIG-I-like receptor-dependent pathway. In addition, we demonstrated that in contrast to USP15 de-ubiquitinating (DUB) activity, USP15-mediated inhibition of IFN signaling was not abolished by mutations eliminating the catalytic activity, indicating that a fraction of USP15-mediated IFN antagonism was independent of the DUB activity. Catalytically inactive USP15 mutants, as did the wild-type protein, disrupted virus-induced interaction of RIG-I and IFN-beta promoter stimulator 1. Taken together, our data demonstrate that USP15 acts as a negative regulator of RIG-I signaling via DUB-dependent and independent mechanisms.
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