Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China; Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.
Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
Mol Cell. 2016 Oct 20;64(2):267-281. doi: 10.1016/j.molcel.2016.08.029. Epub 2016 Sep 29.
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.
TBK1 是 I 型干扰素（IFN）信号通路的一个组成部分，但其活性和降解的调控机制仍知之甚少。本文报道 USP38 通过靶向 TBK1 的活性形式进行降解，在体外和体内负调控 I 型 IFN 信号。USP38 特异性地在 Lys670 处从 TBK1 上切割 K33 连接的多聚泛素链，并允许随后由 DTX4 和 TRIP 介导在同一位置进行 K48 连接的泛素化。USP38 的敲低或敲除增加 K33 连接的泛素化，但它消除 K48 连接的泛素化和 TBK1 的降解，从而增强 I 型 IFN 信号。我们的研究结果确定了 USP38 在负调控 I 型 IFN 信号中的重要作用，并为 USP38 通过 NLRP4 信号体调节 TBK1 泛素化的机制提供了见解。
