Crosstalk between the cGAS DNA Sensor and Beclin-1 Autophagy Protein Shapes Innate Antimicrobial Immune Responses

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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 (cGAS) produces the second messenger cGAMP to initiate the stimulator of interferon genes (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 DNA (dsDNA) stimulation or herpes simplex virus-1 infection, but also enhances autophagy-mediated degradation of cytosolic pathogen DNA 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 DNA. Thus, the cGAS-Beclin-1 interaction shapes innate immune responses by regulating both cGAMP production and autophagy, resulting in well-balanced antimicrobial immune responses.
Publisher
CELL PRESS
Issue Date
2014-02
Language
English
Article Type
Article
Keywords

CYCLIC GMP-AMP; REGULATORY FACTOR 7; CYTOSOLIC DNA; INTRACELLULAR DNA; 2ND-MESSENGER; RUBICON; PHOSPHORYLATION; SYNTHASE; PATHWAY; ATG14L

Citation

CELL HOST & MICROBE, v.15, no.2, pp.228 - 238

ISSN
1931-3128
DOI
10.1016/j.chom.2014.01.009
URI
http://hdl.handle.net/10203/190181
Appears in Collection
BS-Journal Papers(저널논문)
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