1. Oligoadenylate-Synthetase-Family Protein OASL Inhibits Activity of the DNA Sensor cGAS during DNA Virus Infection to Limit Interferon Production
- Author
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Robert A. Parise, Arundhati Ghosh, Baoyu Zhao, Lulu Shao, Pingwei Li, Jan H. Beumer, Bharat Behl, Vijay A. K. Rathinam, Neal A. DeLuca, Roderick J. O’Sullivan, Stephen H. Thorne, Nidhi V. Patel, Padmavathi Sampath, Jianzhong Zhu, and Saumendra N. Sarkar
- Subjects
0301 basic medicine ,THP-1 Cells ,viruses ,Immunology ,Context (language use) ,Biology ,Virus Replication ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,RNA Virus Infections ,Interferon ,medicine ,2',5'-Oligoadenylate Synthetase ,Cyclic AMP ,Immunology and Allergy ,Animals ,Humans ,RNA Viruses ,RNA, Small Interfering ,Mice, Knockout ,DNA Viruses ,RNA ,Membrane Proteins ,DNA virus ,RNA virus ,biology.organism_classification ,Molecular biology ,Nucleotidyltransferases ,DNA Virus Infections ,Mice, Inbred C57BL ,030104 developmental biology ,Infectious Diseases ,chemistry ,Viral replication ,030220 oncology & carcinogenesis ,Interferon Type I ,Vaccinia ,DNA ,medicine.drug ,Signal Transduction - Abstract
Interferon-inducible human oligoadenylate synthetase-like (OASL) and its mouse ortholog, Oasl2, enhance RNA-sensor RIG-I-mediated type I interferon (IFN) induction and inhibit RNA virus replication. Here, we show that OASL and Oasl2 have the opposite effect in the context of DNA virus infection. In Oasl2-/- mice and OASL-deficient human cells, DNA viruses such as vaccinia, herpes simplex, and adenovirus induced increased IFN production, which resulted in reduced virus replication and pathology. Correspondingly, ectopic expression of OASL in human cells inhibited IFN induction through the cGAS-STING DNA-sensing pathway. cGAS was necessary for the reduced DNA virus replication observed in OASL-deficient cells. OASL directly and specifically bound to cGAS independently of double-stranded DNA, resulting in a non-competitive inhibition of the second messenger cyclic GMP-AMP production. Our findings define distinct mechanisms by which OASL differentially regulates host IFN responses during RNA and DNA virus infection and identify OASL as a negative-feedback regulator of cGAS.
- Published
- 2018