RINCK-mediated monoubiquitination of cGAS promotes antiviral innate immune responses.
Background
As an important danger signal, the presence of DNA in cytoplasm triggers potent immune responses. Cyclic GMP-AMP synthase (cGAS) is a recently characterized key sensor for cytoplasmic DNA. The engagement of cGAS with DNA leads to the synthesis of a second messenger, cyclic GMP-AMP (cGAMP), which binds and activates the downstream adaptor protein STING to promote type I interferon production. Although cGAS has been shown to play a pivotal role in innate immunity, the exact regulation of cGAS activation is not fully understood.


Results
We report that an E3 ubiquitin ligase, RING finger protein that interacts with C kinase (RINCK, also known as tripartite motif protein 41, TRIM41), is critical for cGAS activation by mediating the monoubiquitination of cGAS. Using CRISPR/Cas9, we generated RINCK-deletion cells and showed that the deficiency of RINCK resulted in dampened interferon production in response to cytosolic DNA. Consistently, the RINCK-deletion cells also exhibited insufficient interferon production upon herpes simplex virus 1, a DNA virus, infection. As a result, the viral load in RINCK-deficient cells was significantly higher than that in wild-type cells. We also found that RINCK deficiency inhibited the up-stream signaling of DNA-triggered interferon production pathway, which was reflected by the phosphorylation of the TANK-binding kinase 1 and the interferon regulatory factor 3. Interestingly, we found that RINCK binds to cGAS and promotes the monoubiquitination of cGAS, thereby positively regulating the cGAS-mediated cGAMP synthesis.


Conclusions
Our study reveals that monoubiquitination is an important regulation for cGAS activation and uncovers a critical role of RINCK in the cGAS-mediated innate immunity.
['Liu|Zhao-Shan|ZS|', 'Zhang|Zi-Yu|ZY|', 'Cai|Hong|H|', 'Zhao|Ming|M|', 'Mao|Jie|J|', 'Dai|Jiang|J|', 'Xia|Tian|T|', 'Zhang|Xue-Min|XM|', 'Li|Tao|T|0000-0002-0746-8322']
Monoubiquitination cGAS Innate immunity RINCK Antiviral immunity