Structural basis for concerted recruitment and activation of IRF-3 by innate immune adaptor proteins | Academic Article individual record
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.

author list (cited authors)
Zhao, B., Shu, C., Gao, X., Sankaran, B., Du, F., Shelton, C. L., ... Li, P.
publication date
2016
keywords
  • Type I Interferon
  • Rotavirus
  • Creb-binding Protein
  • Transcription Factor
  • Interferon Regulatory Factor-3
  • Crystal Structure
  • Viral Nonstructural Proteins
  • Signaling
  • Adaptor Proteins, Signal Transducing
  • Immune Evasion
  • Innate Immunity
  • Membrane Proteins
  • Rotavirus Infections
  • Protein Domains
  • Immunity, Innate
  • Humans
  • Amino Acid Motifs
  • Adaptor Proteins, Vesicular Transport
altmetric score

1.0

citation count

38