USP19 Inhibits TNF-α- and IL-1β-Triggered NF-κB Activation by Deubiquitinating TAK1
USP19 Inhibits TNF-α- and IL-1β-Triggered NF-κB Activation by Deubiquitinating TAK1
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USP19 通过去泛素化 TAK1 抑制 TNF-α 和 IL-1 β 触发的 NF-kappa B 激活
DOI：
10.4049/jimmunol.1900083
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发表时间：
2019-07-01
影响因子：
4.4
通讯作者：
Shu, Hong-Bing
中科院分区：
文献类型：
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作者：
Lei, Cao-Qi;Wu, Xin;Shu, Hong-Bing
泛素化和去泛素化的动态调控在tgf - β -活化激酶1 （TAK1）介导的NF-kappa B活化中起重要作用，调控各种生理和病理事件。我们发现泛素特异性蛋白酶（USP）19是tnf - α和IL-1 β通过去泛素化TAK1触发的NF-kappa B激活的负调节因子。USP19过表达而非其酶失活突变体抑制tnf - α -和IL-1 β触发的NF-kappa B激活和下游基因的转录，而USP19缺乏则具有相反的作用。与野生型小鼠相比，Usp19（-/-）小鼠产生更高水平的炎症细胞因子，更容易受到tnf - α和IL-1 β引发的败血症死亡的影响。从机制上讲，USP19以tnf - α或IL-1 β依赖的方式与TAK1相互作用，并特异性地从TAK1上解配K63-和k27连接的多泛素链，导致TAK1活性受损和TAK1- tab2 /3复合物的破坏。我们的发现为炎症反应衰减的复杂分子机制提供了新的见解。
The dynamic regulations of ubiquitination and deubiquitination play important roles in TGF-beta-activated kinase 1 (TAK1)-mediated NF-kappa B activation, which regulates various physiological and pathological events. We identified ubiquitin-specific protease (USP)19 as a negative regulator of TNF-alpha- and IL-1 beta-triggered NF-kappa B activation by deubiquitinating TAK1. Overexpression of USP19 but not its enzymatic inactive mutant inhibited TNF-alpha- and IL-1 beta-triggered NF-kappa B activation and transcription of downstream genes, whereas USP19 deficiency had the opposite effects. Usp19(-/-) mice produced higher levels of inflammatory cytokines and were more susceptible to TNF-alpha- and IL-1 beta-triggered septicemia death compared with their wild-type littermates. Mechanistically, USP19 interacted with TAK1 in a TNF-alpha- or IL-1 beta-dependent manner and specifically deconjugated K63- and K27-linked polyubiquitin chains from TAK1, leading to the impairment of TAK1 activity and the disruption of the TAK1-TAB2/3 complex. Our findings provide new insights to the complicated molecular mechanisms of the attenuation of the inflammatory response.