OTUD4 is a phospho-activated K63 deubiquitinase that regulates MyD88-dependent signaling

Abstract from the manuscript: (Zhao Y et al., Molecular Cell, 2018)

Ubiquitination is a major mechanism that regulates numerous cellular processes, including autophagy, DNA damage signaling, and inflammation. While hundreds of ubiquitin ligases exist to conjugate ubiquitin onto substrates, approximately 100 deubiquitinases are encoded by the human genome. Thus, deubiquitinases are likely regulated by unidentified mechanisms to target distinct substrates and cellular functions. Here, we demonstrate that the deubiquitinase OTUD4, which nominally encodes a K48-specific deubiquitinase, is phosphorylated near its catalytic domain, activating a latent K63-specific deubiquitinase. Besides phosphorylation, this latter activity requires an adjacent ubiquitin-interacting motif, which increases the affinity of OTUD4 for K63-linked chains. We reveal the Toll-like receptor (TLR)-associated factor MyD88 as a target of this K63 deubiquitinase activity. Consequently, TLR-mediated activation of NF-κB is negatively regulated by OTUD4, and macrophages from Otud4-/- mice exhibit increased inflammatory signaling upon TLR stimulation. Our results reveal insights into how a deubiquitinase may modulate diverse processes through post-translational modification.

摘要摘自文献：(赵宇等，《分子细胞》，2018年)
泛素化是调节众多细胞过程的主要机制，包括自噬、DNA损伤信号传导和炎症。尽管存在数百种泛素连接酶将泛素连接到底物上，但人类基因组编码的去泛素化酶约为100种。因此，去泛素化酶很可能通过未知的机制进行调节，以靶向不同的底物和细胞功能。在此，我们展示了去泛素化酶OTUD4，它原本编码一种K48特异性去泛素化酶，在其催化结构域附近发生磷酸化，激活了潜在的K63特异性去泛素化酶。除了磷酸化外，这种后者的活性还需要一个相邻的泛素相互作用基序，该基序增加了OTUD4对K63连接链的亲和力。我们发现Toll样受体（TLR）相关因子MyD88是该K63去泛素化酶活性的靶点。因此，TLR介导的NF-κB激活被OTUD4负调节，Otud4-/-小鼠的巨噬细胞在TLR刺激下表现出增多的炎症信号传导。我们的研究结果揭示了去泛素化酶如何通过翻译后修饰调节多种过程。

搜集汇总

背景与挑战

背景概述

该数据集聚焦于OTUD4作为磷酸化激活的K63去泛素化酶的功能研究，揭示了其通过磷酸化和邻近泛素相互作用基序调控K63链特异性活性。研究发现OTUD4负调控MyD88依赖的TLR信号通路，抑制NF-κB激活和炎症反应，为理解去泛素化酶的翻译后修饰机制提供了新见解。