2. Academic Validation
  3. Cutting Edge: USP27X Deubiquitinates and Stabilizes the DNA Sensor cGAS to Regulate Cytosolic DNA-Mediated Signaling

Cutting Edge: USP27X Deubiquitinates and Stabilizes the DNA Sensor cGAS to Regulate Cytosolic DNA-Mediated Signaling

  • J Immunol. 2019 Oct 15;203(8):2049-2054. doi: 10.4049/jimmunol.1900514.
Yunyun Guo 1,  Fei Jiang 1,  Lingli Kong 1,  Bingqing Li 2,  Yinlong Yang 2,  Lei Zhang 1,  Bingyu Liu 1,  Yi Zheng 1,  Chengjiang Gao 3
Affiliations

Affiliations

  • 1 Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan, Shandong 250012, People's Republic of China; and.
  • 2 Key Laboratory of Rare and Uncommon Diseases, Department of Microbiology, Institute of Basic Medicine, Shandong First Medical Sciences, Jinan, Shandong 250062, People's Republic of China.
  • 3 Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Biomedical Sciences, Shandong University, Jinan, Shandong 250012, People's Republic of China; and [email protected].
PMID: 31534008 DOI: 10.4049/jimmunol.1900514
Abstract

Cyclic GMP-AMP Synthase (cGAS), a cytosolic DNA sensor, catalyzes the formation of the second messenger 2'3'-cGAMP that binds to STING and triggers the type I IFN signaling. Activation of cGAS can be modulated by several protein posttranslational modifications, including ubiquitination. However, the cGAS activation regulated by protein deubiquitination remains poorly understood. In this study, we identified that Deubiquitinase USP27X could interact with cGAS and cleave K48-linked polyubiquitination chains from cGAS, leading to cGAS stabilization. Consistently, knockout of Usp27x in mice macrophages resulted in an accelerated turnover of cGAS, decreased cGAMP production, phosphorylation of TBK1 and IRF3, and IFN-β production. Furthermore, Usp27x knockout mice macrophages showed impaired innate Antiviral responses against HSV type 1 Infection. Our data suggest that USP27X is a novel regulator of the cGAS-STING cytosolic DNA sensing pathway.

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