Phosphorylated dimeric IRF3 then is translocated into the nucleus where it induces the expression of type I IFNs and several other inflammatory cytokines and chemokines ( 9).ĬGAS senses DNA from invading pathogens and triggers host immune defenses. After trafficking from the endoplasmic reticulum (ER) to the Golgi, activated STING recruits TANK-binding kinase 1 (TBK1) to promote TBK1 autophosphorylation, STING phosphorylation at Ser366 and subsequent recruitment and phosphorylation of interferon regulatory factor 3 (IRF3) ( 6–8). Upon DNA binding, cGAS becomes enzymatically active and produces cyclic GMP-AMP (cGAMP), a second messenger that binds the stimulator of the interferon (IFN) gene (STING, also known as TMEM173), leading to conformational changes that trigger oligomerization and activation ( 2–5). In summary, the positive role played by USP15-mediated cGAS activation may be a novel regulatory mechanism in the fine-tuning of innate immunity.Īs a pattern recognition receptor (PRR), cyclic GMP-AMP synthase (cGAS) recognizes double-stranded DNA (dsDNA) and plays essential roles in innate immunity ( 1). Upon DNA stimulation, USP15 was induced to express and boost cGAS activation, functioning as an efficient amplifier in innate immune signal transduction. In the absence of DNA, USP15 drove cGAS dimerization and liquid condensation through the USP15 intrinsic disordered region (IDR), which prepared cGAS for a rapid response to DNA. Specifically, USP15 deubiquitylated cGAS and promoted its activation.

USP15 promoted DNA-induced cGAS activation and downstream innate immune responses through a positive feedback mechanism.

In this study, we identified USP15 as a cGAS-interacting partner. However, the mechanism by which cGAS activation is controlled remains to be better understood. cGAS activity must be properly regulated to maintain immune homeostasis. Double-stranded DNA (dsDNA) is recognized as a danger signal by cyclic GMP-AMP synthase (cGAS), which triggers innate immune responses.

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