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Cell Host Microbe. 2015 Sep 9;18(3):333-44. doi: 10.1016/j.chom.2015.07.015. Epub 2015 Aug 27.

Inhibition of cGAS DNA Sensing by a Herpesvirus Virion Protein.

Author information

1
Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
2
Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA.
3
Viral Oncology Section, AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
4
Division of Molecular and Experimental Surgery, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen 91054, Germany.
5
Institute of Clinical and Molecular Virology, University of Erlangen-Nürnberg, Schlossgarten 4, D-91054 Erlangen, Germany.
6
Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA; Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306, USA.
7
Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA. Electronic address: fzhu@bio.fsu.edu.

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.

PMID:
26320998
PMCID:
PMC4567405
DOI:
10.1016/j.chom.2015.07.015
[Indexed for MEDLINE]
Free PMC Article

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