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: Zhe Ma, Sarah R Jacobs, John A West, Charles Stopford, Zhigang Zhang, Zoe Davis, Glen N Barber, Britt A Glaunsinger, Dirk P Dittmer, Blossom Damania
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 31 Pg. E4306-15 (Aug 04 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 26199418 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Viral
• IRF1 protein, human
• Interferon Regulatory Factor-1
• Membrane Proteins
• STING1 protein, human
• Viral Proteins
• Interferon-beta
• Protein Serine-Threonine Kinases
• TBK1 protein, human
• Nucleotidyltransferases
• cGAS protein, human

Topics

• Base Sequence
• DNA, Viral (genetics, metabolism)
• Gene Knockdown Techniques
• Herpesvirus 8, Human (physiology)
• Human Umbilical Vein Endothelial Cells (metabolism)
• Humans
• Interferon Regulatory Factor-1 (metabolism)
• Interferon-beta (metabolism)
• Membrane Proteins (metabolism)
• Molecular Sequence Data
• Nucleotide Motifs (genetics)
• Nucleotidyltransferases (metabolism)
• Open Reading Frames (genetics)
• Promoter Regions, Genetic (genetics)
• Protein Binding
• Protein Serine-Threonine Kinases (metabolism)
• Signal Transduction
• Viral Proteins (metabolism)
• Virus Activation
• Virus Latency