期刊
MOLECULAR CELL
卷 64, 期 2, 页码 267-281出版社
CELL PRESS
DOI: 10.1016/j.molcel.2016.08.029
关键词
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资金
- National Key Basic Research Program of China [2014CB910800, 2015CB859800]
- National Natural Science Foundation of China [31370869, 31522018]
- Guangdong Natural Science Funds for Distinguished Young Scholar [S2013050014772]
- Guangdong Innovative Research Team Program [2011Y035, 201001Y0104687244]
- National Cancer Institute (NCI) [CA101795, DA030338]
- National Institute on Drug Abuse (NIDA), NIH
TBK1 is a component of the type I interferon (IFN) signaling pathway, yet the mechanisms controlling its activity and degradation remain poorly understood. Here we report that USP38 negatively regulates type I IFN signaling by targeting the active form of TBK1 for degradation in vitro and in vivo. USP38 specifically cleaves K33-linked poly-ubiquitin chains from TBK1 at Lys670, and it allows for subsequent K48-linked ubiquitination at the same position mediated by DTX4 and TRIP. Knockdown or knockout of USP38 increases K33-linked ubiquitination, but it abrogates K48-linked ubiquitination and degradation of TBK1, thus enhancing type I IFN signaling. Our findings identify an essential role for USP38 in negatively regulating type I IFN signaling, and they provide insights into the mechanisms by which USP38 regulates TBK1 ubiquitination through the NLRP4 signalosome.
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