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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 24; pp. E3403 - E3412
• Main Authors: Zhao, Baoyu, Shu, Chang, Gao, Xinsheng, Sankaran, Banumathi, Du, Fenglei, Shelton, Catherine L., Herr, Andrew B., Ji, Jun-Yuan, Li, Pingwei
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 14.06.2016; National Academy of Sciences, Washington, DC (United States)
• Series: PNAS Plus
• Subjects: 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; 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; type I interferon; crystal structure; transcription factor; signaling; innate immunity
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1603269113

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.