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Title: Structural basis for concerted recruitment and activation of IRF-3 by innate immune adaptor proteins

Type I IFNs are key cytokines mediating innate antiviral immunity. cGMP-AMP synthase, ritinoic acid-inducible protein 1 (RIG-I)–like receptors, and Toll-like receptors recognize microbial double-stranded (ds)DNA, dsRNA, and LPS to induce the expression of type I IFNs. These signaling pathways converge at the recruitment and activation of the transcription factor IRF-3 (IFN regulatory factor 3). The adaptor proteins STING (stimulator of IFN genes), MAVS (mitochondrial antiviral signaling), and TRIF (TIR domain-containing adaptor inducing IFN-β) mediate the recruitment of IRF-3 through a conserved pLxIS motif. Here in this paper, we show that the pLxIS motif of phosphorylated STING, MAVS, and TRIF binds to IRF-3 in a similar manner, whereas residues upstream of the motif confer specificity. The structure of the IRF-3 phosphomimetic mutant S386/396E bound to the cAMP response element binding protein (CREB)-binding protein reveals that the pLxIS motif also mediates IRF-3 dimerization and activation. Moreover, rotavirus NSP1 (nonstructural protein 1) employs a pLxIS motif to target IRF-3 for degradation, but phosphorylation of NSP1 is not required for its activity. These results suggest a concerted mechanism for the recruitment and activation of IRF-3 that can be subverted by viral proteins to evade innate immune responses.
Authors:
 [1] ;  [1] ;  [2] ;  [3] ;  [1] ;  [4] ;  [5] ;  [2] ;  [1]
  1. Texas A & M Univ., College Station, TX (United States). Dept. of Biochemistry and Biophysics
  2. Texas A & M Univ., College Station, TX (United States). College of Medicine, Dept. of Molecular and Cellular Medicine
  3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Berkeley Center for Structural Biology, Physical Biosciences Division
  4. Cincinnati Children's Hospital Medical Center, Cincinnati, OH (United States). Center for Systems Immunology, Division of Immunobiology; Cincinnati Children's Hospital Medical Center, Cincinnati, OH (United States). Division of Infectious Diseases
  5. Cincinnati Children's Hospital Medical Center, Cincinnati, OH (United States). Center for Systems Immunology, Division of Immunobiology; Cincinnati Children's Hospital Medical Center, Cincinnati, OH (United States). Division of Infectious Diseases
Publication Date:
Grant/Contract Number:
AC02-05CH11231
Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 113; Journal Issue: 24; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Research Org:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; innate immunity; signaling; type I interferon; transcription factor; crystal structure
OSTI Identifier:
1379399