title: Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses.
abstract: Infection of cells with DNA viruses triggers innate immune responses mediated by DNA sensors. cGMP-AMP synthase (cGAS) is a key DNA sensor that produces the cyclic dinucleotide cGMP-AMP (cGAMP) upon activation, which binds to and activates stimulator of interferon genes (STING), leading to IFN production and an antiviral response. Kaposi's sarcoma-associated herpesvirus (KSHV) is a DNA virus that is linked to several human malignancies. We report that KSHV infection activates the cGAS-STING pathway, and that cGAS and STING also play an important role in regulating KSHV reactivation from latency. We screened KSHV proteins for their ability to inhibit this pathway and identified six viral proteins that block IFN-β activation through this pathway. This study is the first report identifying multiple viral proteins encoded by a human DNA virus that inhibit the cGAS-STING DNA sensing pathway. One such protein, viral interferon regulatory factor 1 (vIRF1), targets STING by preventing it from interacting with TANK binding kinase 1 (TBK1), thereby inhibiting STING's phosphorylation and concomitant activation, resulting in an inhibition of the DNA sensing pathway. Our data provide a unique mechanism for the negative regulation of STING-mediated DNA sensing. Moreover, the depletion of vIRF1 in the context of KSHV infection prevented efficient viral reactivation and replication, and increased the host IFN response to KSHV. The vIRF1-expressing cells also inhibited IFN-β production following infection with DNA pathogens. Collectively, our results demonstrate that gammaherpesviruses encode inhibitors that block cGAS-STING-mediated antiviral immunity, and that modulation of this pathway is important for viral transmission and the lifelong persistence of herpesviruses in the human population.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors.forename: Zhe
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Jacobs
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors.forename: John A
authors.initials: JA
authors.lastname: West
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors.forename: Charles
authors.initials: C
authors.lastname: Stopford
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Plant and Microbial Biology, University of California, Berkeley, CA 94720; Division of Infectious Diseases and Immunity, School of Public Health, University of California, Berkeley, CA 94720;
authors.forename: Zoe
authors.initials: Z
authors.lastname: Davis
authors.affiliation: Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL 33136;
authors.forename: Glen N
authors.initials: GN
authors.lastname: Barber
authors.affiliation: Department of Plant and Microbial Biology, University of California, Berkeley, CA 94720;
authors.forename: Britt A
authors.initials: BA
authors.lastname: Glaunsinger
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; University of North Carolina Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors.forename: Dirk P
authors.initials: DP
authors.lastname: Dittmer
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; University of North Carolina Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 damania@med.unc.edu.
authors.forename: Blossom
authors.initials: B
authors.lastname: Damania
mesh_terms: D001483:Base Sequence; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D019288:Herpesvirus 8, Human / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D059372:Nucleotide Motifs / Q000235:genetics; D009713:Nucleotidyltransferases / Q000378:metabolism*; D016366:Open Reading Frames / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014764:Viral Proteins / Q000378:metabolism; D014775:Virus Activation; D017735:Virus Latency; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D004279:DNA, Viral; D050856:Interferon Regulatory Factor-1; D016899:Interferon-beta; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; D017346:Protein Serine-Threonine Kinases; D014764:Viral Proteins; C494257:IRF1 protein, human; C532857:STING1 protein, human; D000099197:STING Protein; C403191:TBK1 protein, human; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
keywords: KSHV; STING; cGAS; innate immunity; vIRF1