2. Academic Validation
  3. Structural basis for concerted recruitment and activation of IRF-3 by innate immune adaptor proteins

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

  • Proc Natl Acad Sci U S A. 2016 Jun 14;113(24):E3403-12. doi: 10.1073/pnas.1603269113.
Baoyu Zhao 1,  Chang Shu 2,  Xinsheng Gao 3,  Banumathi Sankaran 4,  Fenglei Du 1,  Catherine L Shelton 5,  Andrew B Herr 5,  Jun-Yuan Ji 3,  Pingwei Li 2
Affiliations

Affiliations

  • 1 Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843;
  • 2 Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843; [email protected] [email protected].
  • 3 Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, TX 77843;
  • 4 Berkeley Center for Structural Biology, Physical Biosciences Division, Lawrence Berkeley Laboratory, Berkeley, CA 94720;
  • 5 Division of Immunobiology, Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
PMID: 27302953 DOI: 10.1073/pnas.1603269113
Abstract

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 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.

Keywords

crystal structure; innate immunity; signaling; transcription factor; type I interferon.

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