Abstract
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 language | English (US) |
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Pages (from-to) | 267-281 |
Number of pages | 15 |
Journal | Molecular Cell |
Volume | 64 |
Issue number | 2 |
DOIs | |
State | Published - Oct 20 2016 |
Keywords
- K33 ubiquitination
- TBK1 degradation
- TBK1 ubiquitination
- USP38 deubiquitination
- innate immune signaling
- type I interferon response
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology