TitleSystems-based analysis of RIG-I-dependent signalling identifies KHSRP as an inhibitor of RIG-I receptor activation.
Publication TypeJournal Article
Year of Publication2017
AuthorsSoonthornvacharin, S, Rodriguez-Frandsen, A, Zhou, Y, Galvez, F, Huffmaster, NJ, Tripathi, S, Balasubramaniam, VRMT, Inoue, A, de Castro, E, Moulton, HM, Stein, DA, Sánchez-Aparicio, MTeresa, De Jesus, PD, Nguyen, Q, König, R, Krogan, NJ, García-Sastre, A, Yoh, SM, Chanda, SK
JournalNat Microbiol
Date Published2017 Mar 01
KeywordsDEAD Box Protein 58, HEK293 Cells, Humans, Immunity, Innate, Influenza A Virus, H1N1 Subtype, Protein Binding, Protein Interaction Mapping, Protein Interaction Maps, RNA, Viral, RNA-Binding Proteins, Signal Transduction, Trans-Activators

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.

Alternate JournalNat Microbiol
PubMed ID28248290
PubMed Central IDPMC5338947
Grant ListHHSN272201400008C / AI / NIAID NIH HHS / United States
P30 CA030199 / CA / NCI NIH HHS / United States
P50 GM085764 / GM / NIGMS NIH HHS / United States
U19 AI106754 / AI / NIAID NIH HHS / United States