title: Inhibition of cGAS DNA Sensing by a Herpesvirus Virion Protein.
abstract: Invading viral DNA can be recognized by the host cytosolic DNA sensor, cyclic GMP-AMP (cGAMP) synthase (cGAS), resulting in production of the second messenger cGAMP, which directs the adaptor protein STING to stimulate production of type I interferons (IFNs). Although several DNA viruses are sensed by cGAS, viral strategies targeting cGAS are virtually unknown. We report here that Kaposi's sarcoma-associated herpesvirus (KSHV) ORF52, an abundant gammaherpesvirus-specific tegument protein, subverts cytosolic DNA sensing by directly inhibiting cGAS enzymatic activity through a mechanism involving both cGAS binding and DNA binding. Moreover, ORF52 homologs in other gammaherpesviruses also inhibit cGAS activity and similarly bind cGAS and DNA, suggesting conserved inhibitory mechanisms. Furthermore, KSHV infection evokes cGAS-dependent responses that can limit the infection, and an ORF52 null mutant exhibits increased cGAS signaling. Our findings reveal a mechanism through which gammaherpesviruses antagonize host cGAS DNA sensing.
authors: Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
authors: Jian-jun
authors: JJ
authors: Wu
authors: Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
authors: Wenwei
authors: W
authors: Li
authors: Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA.
authors: Yaming
authors: Y
authors: Shao
authors: Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
authors: Denis
authors: D
authors: Avey
authors: Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
authors: Bishi
authors: B
authors: Fu
authors: Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
authors: Joseph
authors: J
authors: Gillen
authors: Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA.
authors: Travis
authors: T
authors: Hand
authors: Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
authors: Siming
authors: S
authors: Ma
authors: Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
authors: Xia
authors: X
authors: Liu
authors: Viral Oncology Section, AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors: Wendell
authors: W
authors: Miley
authors: Division of Molecular and Experimental Surgery, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen 91054, Germany.
authors: Andreas
authors: A
authors: Konrad
authors: Institute of Clinical and Molecular Virology, University of Erlangen-Nürnberg, Schlossgarten 4, D-91054 Erlangen, Germany.
authors: Frank
authors: F
authors: Neipel
authors: Division of Molecular and Experimental Surgery, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen 91054, Germany.
authors: Michael
authors: M
authors: Stürzl
authors: Viral Oncology Section, AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors: Denise
authors: D
authors: Whitby
authors: Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA; Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306, USA.
authors: Hong
authors: H
authors: Li
authors: Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA. Electronic address: fzhu@bio.fsu.edu.
authors: Fanxiu
authors: F
authors: Zhu
mesh_terms: D002460:Cell Line; D004279:DNA, Viral / Q000378:metabolism*; D019288:Herpesvirus 8, Human / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D004279:DNA, Viral; D009713:Nucleotidyltransferases; D014764:Viral Proteins; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase