Journal Article

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

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

2016

Overview

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.

• Publisher: National Academy of Sciences,National Academy of Sciences, Washington, DC (United States)
• Subject: 60 APPLIED LIFE SCIENCES / Adaptor Proteins, Signal Transducing - chemistry / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - immunology / Adaptor Proteins, Vesicular Transport - chemistry / Adaptor Proteins, Vesicular Transport - genetics / Adaptor Proteins, Vesicular Transport - immunology / Amino Acid Motifs / BASIC BIOLOGICAL SCIENCES / Binding sites / Biological Sciences / CREB-Binding Protein - chemistry / CREB-Binding Protein - genetics / CREB-Binding Protein - immunology / crystal structure / Cytokines / Gene expression / Humans / Immune Evasion / Immunity, Innate / Immunology and Inflammation / innate immunity / Interferon Regulatory Factor-3 - chemistry / Interferon Regulatory Factor-3 - genetics / Interferon Regulatory Factor-3 - immunology / Membrane Proteins - chemistry / Membrane Proteins - genetics / Membrane Proteins - immunology / Phosphorylation / PNAS Plus / Protein Domains / Proteins / Reoviridae / Rotavirus - chemistry / Rotavirus - genetics / Rotavirus - immunology / Rotavirus Infections - genetics / Rotavirus Infections - immunology / Signal transduction / signaling / transcription factor / type I interferon / Viral Nonstructural Proteins - chemistry / Viral Nonstructural Proteins - genetics / Viral Nonstructural Proteins - immunology