Crosstalk between cGAS DNA sensor and Beclin-1 autophagy protein shapes innate anti-microbial immune responses

• Published in: Cell host & microbe 2014-02, Vol.15 (2), p.228-238
• Main Authors: Liang, Qiming, Seo, Gil Ju, Choi, Youn Jung, Kwak, Mi-Jeong, Ge, Jianning, Rodgers, Mary A, Shi, Mude, Leslie, Benjamin J., Hopfner, Karl-Peter, Ha, Taekjip, Oh, Byung-Ha, Jung, Jae U.
• Format: Article
• Language: English
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2014.01.009

Robust immune responses are essential for eliminating pathogens, but must be metered to avoid prolonged immune activation and potential host damage. Upon recognition of microbial DNA, the cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthetase, or cGAS, produces the second messenger cGAMP to initiate the STING pathway and subsequent interferon (IFN) production. We report that the direct interaction between cGAS and the Beclin-1 autophagy protein not only suppresses cGAMP synthesis to halt IFN production upon double stranded (ds)DNA stimulation or herpes simplex virus-1 infection, but also enhances autophagy-mediated degradation of cytosolic pathogen DNAs to prevent excessive cGAS activation and persistent immune stimulation. Specifically, this interaction releases Rubicon, a negative autophagy regulator, from the Beclin-1 complex, activating phosphatidylinositol 3-kinase class III activity and thereby inducing autophagy to remove cytosolic pathogen DNAs. Thus, the cGAS-Beclin-1 interaction shapes innate immune responses by regulating both cGAMP production and autophagy, resulting in well-balanced anti-microbial immune responses.