title: Akt Kinase-Mediated Checkpoint of cGAS DNA Sensing Pathway.
abstract: Upon DNA stimulation, cyclic GMP-AMP synthase (cGAS) synthesizes the second messenger cyclic GMP-AMP (cGAMP) that binds to the STING, triggering antiviral interferon-β (IFN-β) production. However, it has remained undetermined how hosts regulate cGAS enzymatic activity after the resolution of DNA immunogen. Here, we show that Akt kinase plays a negative role in cGAS-mediated anti-viral immune response. Akt phosphorylated the S291 or S305 residue of the enzymatic domain of mouse or human cGAS, respectively, and this phosphorylation robustly suppressed its enzymatic activity. Consequently, expression of activated Akt led to the reduction of cGAMP and IFN-β production and the increase of herpes simplex virus 1 replication, whereas treatment with Akt inhibitor augmented cGAS-mediated IFN-β production. Furthermore, expression of the phosphorylation-resistant cGAS S291A mutant enhanced IFN-β production upon DNA stimulation, HSV-1 infection, and vaccinia virus infection. Our study identifies an Akt kinase-mediated checkpoint to fine-tune hosts' immune responses to DNA stimulation.
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Gil Ju
authors.initials: GJ
authors.lastname: Seo
authors.affiliation: Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Aerin
authors.initials: A
authors.lastname: Yang
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Tan
authors.affiliation: Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Sungyoon
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Qiming
authors.initials: Q
authors.lastname: Liang
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Younho
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Weiming
authors.initials: W
authors.lastname: Yuan
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Pinghui
authors.initials: P
authors.lastname: Feng
authors.affiliation: Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Hee-Sung
authors.initials: HS
authors.lastname: Park
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: jaeujung@med.usc.edu.
authors.forename: Jae U
authors.initials: JU
authors.lastname: Jung
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004279:DNA, Viral / Q000235:genetics*; D057809:HEK293 Cells; D018259:Herpesvirus 1, Human / Q000502:physiology; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009713:Nucleotidyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015290:Second Messenger Systems; D014779:Virus Replication; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D004279:DNA, Viral; D016899:Interferon-beta; D009713:Nucleotidyltransferases; D051057:Proto-Oncogene Proteins c-akt; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase