Structural basis for concerted recruitment and activation of IRF-3 by innate immune adaptor proteins. Academic Article uri icon

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.

published proceedings

  • Proc Natl Acad Sci U S A

altmetric score

  • 2.25

author list (cited authors)

  • Zhao, B., Shu, C., Gao, X., Sankaran, B., Du, F., Shelton, C. L., ... Li, P.

citation count

  • 67

complete list of authors

  • Zhao, Baoyu||Shu, Chang||Gao, Xinsheng||Sankaran, Banumathi||Du, Fenglei||Shelton, Catherine L||Herr, Andrew B||Ji, Jun-Yuan||Li, Pingwei

publication date

  • June 2016