USP38 Inhibits Type I Interferon Signaling by Editing TBK1 Ubiquitination through NLRP4 Signalosome

Meng Lin, Zhiyao Zhao, Zhifen Yang, Qingcai Meng, Peng Tan, Weihong Xie, Yunfei Qin, Rong Fu Wang, Jun Cui

Research output: Contribution to journalArticlepeer-review

77 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)267-281
Number of pages15
JournalMolecular Cell
Issue number2
StatePublished - Oct 20 2016


  • K33 ubiquitination
  • TBK1 degradation
  • TBK1 ubiquitination
  • USP38 deubiquitination
  • innate immune signaling
  • type I interferon response

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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