Antiviral activity of human OASL protein is mediated by enhancing signaling of the RIG-I RNA sensor

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  • Jianzhong Zhu, Cancer Virology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Ukendt
  • Yugen Zhang, Cancer Virology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Ukendt
  • Arundhati Ghosh, Cancer Virology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Ukendt
  • Rolando A Cuevas, Cancer Virology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Ukendt
  • Adriana Forero, Cancer Virology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Ukendt
  • Jayeeta Dhar, Center for Gene Regulation in Health and Disease, and Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA., Ukendt
  • Mikkel Søes Ibsen, Department of Molecular Biology, Aarhus University, Aarhus 8000, Denmark., Danmark
  • Jonathan Leo Schmid-Burgk, Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn 53127, Germany., Ukendt
  • Tobias Schmidt, Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn 53127, Germany., Ukendt
  • Madhavi K Ganapathiraju, Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Ukendt
  • Takashi Fujita, Laboratory of Molecular Genetics, Kyoto University, Kyoto 606-8507, Japan., Ukendt
  • Rune Hartmann
  • Sailen Barik, Center for Gene Regulation in Health and Disease, and Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA., Ukendt
  • Veit Hornung, Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn 53127, Germany., Ukendt
  • Carolyn B Coyne, Cancer Virology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Ukendt
  • Saumendra N Sarkar, Cancer Virology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Electronic address: saumen@pitt.edu., Ukendt

Virus infection is sensed in the cytoplasm by retinoic acid-inducible gene I (RIG-I, also known as DDX58), which requires RNA and polyubiquitin binding to induce type I interferon (IFN) and activate cellular innate immunity. We show that the human IFN-inducible oligoadenylate synthetases-like (OASL) protein has antiviral activity and mediates RIG-I activation by mimicking polyubiquitin. Loss of OASL expression reduced RIG-I signaling and enhanced virus replication in human cells. Conversely, OASL expression suppressed replication of a number of viruses in a RIG-I-dependent manner and enhanced RIG-I-mediated IFN induction. OASL interacted and colocalized with RIG-I, and through its C-terminal ubiquitin-like domain specifically enhanced RIG-I signaling. Bone-marrow-derived macrophages from mice deficient for Oasl2 showed that among the two mouse orthologs of human OASL, Oasl2 is functionally similar to human OASL. Our findings show a mechanism by which human OASL contributes to host antiviral responses by enhancing RIG-I activation.

OriginalsprogEngelsk
TidsskriftImmunity
Vol/bind40
Nummer6
Sider (fra-til)936-948
Antal sider13
ISSN1074-7613
DOI
StatusUdgivet - 19 jun. 2014

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