Crosstalk between the cGAS DNA sensor and Beclin-1 autophagy protein shapes innate antimicrobial immune responses

Cell Host Microbe. 2014 Feb 12;15(2):228-38. 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 (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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / immunology*
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy
  • Autophagy-Related Proteins
  • Beclin-1
  • Cell Line
  • DNA / immunology*
  • DNA / metabolism
  • Herpesvirus 1, Human / immunology*
  • Humans
  • Immunity, Innate*
  • Interferons / immunology
  • Interferons / metabolism
  • Intracellular Signaling Peptides and Proteins / immunology
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins / immunology*
  • Membrane Proteins / metabolism
  • Mice
  • Nucleotides, Cyclic / metabolism
  • Nucleotidyltransferases / immunology*
  • Nucleotidyltransferases / metabolism
  • Phosphatidylinositol 3-Kinase / metabolism


  • Apoptosis Regulatory Proteins
  • Autophagy-Related Proteins
  • BECN1 protein, human
  • Beclin-1
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Nucleotides, Cyclic
  • RUBCN protein, human
  • cyclic guanosine monophosphate-adenosine monophosphate
  • DNA
  • Interferons
  • Phosphatidylinositol 3-Kinase
  • Nucleotidyltransferases
  • cGAS protein, human