title: Antiviral activity of human OASL protein is mediated by enhancing signaling of the RIG-I RNA sensor.
abstract: 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.
authors.affiliation: 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.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Yugen
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Arundhati
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: 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.
authors.forename: Rolando A
authors.initials: RA
authors.lastname: Cuevas
authors.affiliation: 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.
authors.forename: Adriana
authors.initials: A
authors.lastname: Forero
authors.affiliation: Center for Gene Regulation in Health and Disease, and Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA.
authors.forename: Jayeeta
authors.initials: J
authors.lastname: Dhar
authors.affiliation: Department of Molecular Biology, Aarhus University, Aarhus 8000, Denmark.
authors.forename: Mikkel Søes
authors.initials: MS
authors.lastname: Ibsen
authors.affiliation: Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn 53127, Germany.
authors.forename: Jonathan Leo
authors.initials: JL
authors.lastname: Schmid-Burgk
authors.affiliation: Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn 53127, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Madhavi K
authors.initials: MK
authors.lastname: Ganapathiraju
authors.affiliation: Laboratory of Molecular Genetics, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Department of Molecular Biology, Aarhus University, Aarhus 8000, Denmark.
authors.forename: Rune
authors.initials: R
authors.lastname: Hartmann
authors.affiliation: Center for Gene Regulation in Health and Disease, and Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA.
authors.forename: Sailen
authors.initials: S
authors.lastname: Barik
authors.affiliation: Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn 53127, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.affiliation: 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.
authors.forename: Carolyn B
authors.initials: CB
authors.lastname: Coyne
authors.affiliation: 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.
authors.forename: Saumendra N
authors.initials: SN
authors.lastname: Sarkar
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000276:immunology*; D004266:DNA Virus Infections / Q000276:immunology*; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D025821:Polyubiquitin; D011485:Protein Binding / Q000276:immunology; D034622:RNA Interference; D012327:RNA Virus Infections / Q000276:immunology*; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000276:immunology; D014779:Virus Replication / Q000276:immunology
chemical_list: C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; D025821:Polyubiquitin; C115020:OASL protein, human; C475084:Oasl2 protein, mouse; D015088:2',5'-Oligoadenylate Synthetase; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases