1. Academic Validation
  2. USP19 (ubiquitin specific peptidase 19) promotes TBK1 (TANK-binding kinase 1) degradation via chaperone-mediated autophagy

USP19 (ubiquitin specific peptidase 19) promotes TBK1 (TANK-binding kinase 1) degradation via chaperone-mediated autophagy

  • Autophagy. 2022 Apr;18(4):891-908. 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
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory Of Regional Immunity And Diseases, Department Of Immunology, Shenzhen University School Of Medicine, Shenzhen, China.
  • 2 Institute Of Immunology, Zhejiang University School Of Medicine, Hangzhou, China.
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.

Keywords

Antiviral immunity; autophagic degradation; hspa8/hsc70; lamp2a; type i interferon.

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