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USP19 (ubiquitin specific peptidase 19) promotes TBK1 (TANK-binding kinase 1) degradation via chaperone-mediated autophagy
Autophagy ( IF 14.6 ) Pub Date : 2021-08-26 , DOI: 10.1080/15548627.2021.1963155
Xibao Zhao 1 , Qianqian Di 1 , Juan Yu 2 , Jiazheng Quan 1 , Yue Xiao 1 , Huihui Zhu 2 , Hongrui Li 2 , Jing Ling 2 , Weilin Chen 1
Affiliation  

ABSTRACT

TBK1 (TANK-binding kinase 1) is an essential receptor protein required for the innate immune response, but the mechanisms underlying TBK1 stability, especially those regulated via autophagy, remain poorly understood. Here, we demonstrate that USP19 (ubiquitin specific peptidase 19) interacts with and promotes TBK1 lysosomal degradation via chaperone-mediated autophagy (CMA). We observed that TBK1 had a canonical CMA motif, knocking down key proteins involved in CMA (HSPA8/HSC70 or LAMP2A) or inhibiting CMA-prevented USP19-mediated TBK1 degradation. Furthermore, USP19 deficiency in macrophages caused an elevation of TBK1 and the activation of the type-I interferon signaling pathway after vesicular stomatitis virus (VSV) infection. Consistently, macrophage-specific usp19 knockout in mice resulted in attenuated VSV replication and resistance to VSV infection in vivo. Altogether, our results suggest that USP19 is a key regulator of TBK1 and uncovers a previously uncharacterized role for USP19 in CMA-mediated TBK1 degradation and infectious diseases.



中文翻译:

USP19(泛素特异性肽酶 19)通过伴侣介导的自噬促进 TBK1(TANK 结合激酶 1)降解

摘要

TBK1(TANK 结合激酶 1)是先天免疫反应所需的必需受体蛋白,但 TBK1 稳定性的机制,尤其是那些通过自噬调节的机制,仍然知之甚少。在这里,我们证明 USP19(泛素特异性肽酶 19)通过伴侣介导的自噬 (CMA) 与 TBK1 溶酶体降解相互作用并促进其降解。我们观察到 TBK1 具有典型的 CMA 基序,可敲除参与 CMA 的关键蛋白(HSPA8/HSC70 或 LAMP2A)或抑制 CMA 阻止的 USP19 介导的 TBK1 降解。此外,巨噬细胞中的 USP19 缺乏导致水疱性口炎病毒 (VSV) 感染后 TBK1 升高和 I 型干扰素信号通路的激活。一致地,巨噬细胞特异性usp19小鼠中的基因敲除导致体内VSV 复制和对 VSV 感染的抵抗力减弱。总之,我们的研究结果表明,USP19 是 TBK1 的关键调节因子,并揭示了 USP19 在 CMA 介导的 TBK1 降解和传染病中以前未被表征的作用。

更新日期:2021-08-26
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