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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.

journal_name

Nat Microbiol

journal_title

Nature microbiology

authors

Soonthornvacharin S,Rodriguez-Frandsen A,Zhou Y,Galvez F,Huffmaster NJ,Tripathi S,Balasubramaniam VR,Inoue A,de Castro E,Moulton H,Stein DA,Sánchez-Aparicio MT,De Jesus PD,Nguyen Q,König R,Krogan NJ,García-Sastre A,Yoh

doi

10.1038/nmicrobiol.2017.22

subject

Has Abstract

pub_date

2017-03-01 00:00:00

pages

17022

issn

2058-5276

pii

nmicrobiol201722

journal_volume

2

pub_type

杂志文章

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