title: Systems-based analysis of RIG-I-dependent signalling identifies KHSRP as an inhibitor of RIG-I receptor activation.
abstract: Retinoic acid-inducible gene I (RIG-I) receptor recognizes 5'-triphosphorylated RNA and triggers a signalling cascade that results in the induction of type-I interferon (IFN)-dependent responses. Its precise regulation represents a pivotal balance between antiviral defences and autoimmunity. To elucidate the cellular cofactors that regulate RIG-I signalling, we performed two global RNA interference analyses to identify both positive and negative regulatory nodes operating on the signalling pathway during virus infection. These factors were integrated with experimentally and computationally derived interactome data to build a RIG-I protein interaction network. Our analysis revealed diverse cellular processes, including the unfolded protein response, Wnt signalling and RNA metabolism, as critical cellular components governing innate responses to non-self RNA species. Importantly, we identified K-Homology Splicing Regulatory Protein (KHSRP) as a negative regulator of this pathway. We find that KHSRP associates with the regulatory domain of RIG-I to maintain the receptor in an inactive state and attenuate its sensing of viral RNA (vRNA). Consistent with increased RIG-I antiviral signalling in the absence of KHSRP, viral replication is reduced when KHSRP expression is knocked down both in vitro and in vivo. Taken together, these data indicate that KHSRP functions as a checkpoint regulator of the innate immune response to pathogen challenge.
authors.affiliation: Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.|The San Diego Center for Systems Biology (SDCSB), La Jolla, California 92093, USA.|Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Soonthornvacharin
authors.affiliation: Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.|The San Diego Center for Systems Biology (SDCSB), La Jolla, California 92093, USA.
authors.forename: Ariel
authors.identifier: http://orcid.org/0000-0001-6850-5003
authors.initials: A
authors.lastname: Rodriguez-Frandsen
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors.forename: Yingyao
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.|The San Diego Center for Systems Biology (SDCSB), La Jolla, California 92093, USA.
authors.forename: Felipe
authors.initials: F
authors.lastname: Galvez
authors.affiliation: Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.|The San Diego Center for Systems Biology (SDCSB), La Jolla, California 92093, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Huffmaster
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, New York 10029, USA.|Global Health and Emerging Pathogen Institute, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, New York 10029, USA.
authors.forename: Shashank
authors.initials: S
authors.lastname: Tripathi
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, New York 10029, USA.|Global Health and Emerging Pathogen Institute, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, New York 10029, USA.
authors.forename: Vinod R M T
authors.initials: VR
authors.lastname: Balasubramaniam
authors.affiliation: Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Inoue
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, New York 10029, USA.|Global Health and Emerging Pathogen Institute, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, New York 10029, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: de Castro
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University Corvallis, 450 SW 30th Street, Oregon 97331, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Moulton
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University Corvallis, 450 SW 30th Street, Oregon 97331, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Stein
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, New York 10029, USA.|Global Health and Emerging Pathogen Institute, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, New York 10029, USA.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Sánchez-Aparicio
authors.affiliation: Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.|The San Diego Center for Systems Biology (SDCSB), La Jolla, California 92093, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: De Jesus
authors.affiliation: Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.|The San Diego Center for Systems Biology (SDCSB), La Jolla, California 92093, USA.
authors.forename: Quy
authors.initials: Q
authors.lastname: Nguyen
authors.affiliation: Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.|Host-Pathogen-Interactions, Paul-Ehrlich-Institute, German Center for Infection Research (DZIF), Paul-Ehrlich-Straße 51-59, 63225 Langen, Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: König
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California San Francisco, 1700 4th Street, Byers Hall 308D, Box 2530, San Francisco, California 94158, USA.
authors.forename: Nevan J
authors.initials: NJ
authors.lastname: Krogan
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, New York 10029, USA.|Global Health and Emerging Pathogen Institute, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, New York 10029, USA.|Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, New York 10029, USA.
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.affiliation: Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.|The San Diego Center for Systems Biology (SDCSB), La Jolla, California 92093, USA.
authors.forename: Sunnie M
authors.initials: SM
authors.lastname: Yoh
authors.affiliation: Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.|The San Diego Center for Systems Biology (SDCSB), La Jolla, California 92093, USA.
authors.forename: Sumit K
authors.initials: SK
authors.lastname: Chanda
mesh_terms: D000071457:DEAD Box Protein 58 / Q000037:antagonists & inhibitors*; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D011485:Protein Binding; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D012367:RNA, Viral / Q000276:immunology*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D011971:Receptors, Immunologic; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: C105789:KHSRP protein, human; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D011971:Receptors, Immunologic; D015534:Trans-Activators; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58