title: Crosstalk between the cGAS DNA sensor and Beclin-1 autophagy protein shapes innate antimicrobial immune responses.
abstract: 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.
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors: Qiming
authors: Q
authors: Liang
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors: Gil Ju
authors: GJ
authors: Seo
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors: Youn Jung
authors: YJ
authors: Choi
authors: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors: Mi-Jeong
authors: MJ
authors: Kwak
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors: Jianning
authors: J
authors: Ge
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors: Mary A
authors: MA
authors: Rodgers
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors: Mude
authors: M
authors: Shi
authors: Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Howard Hughes Medical Institute, Urbana, IL 61801, USA.
authors: Benjamin J
authors: BJ
authors: Leslie
authors: Center for Integrated Protein Science and Munich Center for Advanced Photonics at the Gene Center, Ludwig-Maximilians University, 81377 Munich, Germany.
authors: Karl-Peter
authors: KP
authors: Hopfner
authors: Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Howard Hughes Medical Institute, Urbana, IL 61801, USA.
authors: Taekjip
authors: T
authors: Ha
authors: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors: Byung-Ha
authors: BH
authors: Oh
authors: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: jaeujung@med.usc.edu.
authors: Jae U
authors: JU
authors: Jung
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000276:immunology* / Q000378:metabolism; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; D002460:Cell Line; D004247:DNA / Q000276:immunology* / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D007372:Interferons / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D009712:Nucleotides, Cyclic / Q000378:metabolism; D009713:Nucleotidyltransferases / Q000276:immunology* / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; D004247:DNA; D007372:Interferons; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009712:Nucleotides, Cyclic; D009713:Nucleotidyltransferases; D058539:Phosphatidylinositol 3-Kinase; C491997:BECN1 protein, human; C552537:RUBCN protein, human; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase