Structural basis for concerted recruitment and activation of IRF-3 by innate immune adaptor proteins.
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.
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843;
Baoyu
B
Zhao
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843; pingwei@tamu.edu cshu2005@hotmail.com.
Chang
C
Shu
Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, TX 77843;
Xinsheng
X
Gao
Berkeley Center for Structural Biology, Physical Biosciences Division, Lawrence Berkeley Laboratory, Berkeley, CA 94720;
Banumathi
B
Sankaran
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843;
Fenglei
F
Du
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.
Catherine L
CL
Shelton
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.
Andrew B
AB
Herr
Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, TX 77843;
Jun-Yuan
JY
Ji
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843; pingwei@tamu.edu cshu2005@hotmail.com.
Pingwei
P
Li
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D020816:Amino Acid Motifs; D050882:CREB-Binding Protein / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D006801:Humans; D057131:Immune Evasion; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D000072417:Protein Domains; D012401:Rotavirus / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D012400:Rotavirus Infections / Q000235:genetics / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D000099197:STING Protein
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D050882:CREB-Binding Protein; D050838:Interferon Regulatory Factor-3; D008565:Membrane Proteins; D017361:Viral Nonstructural Proteins; C494232:IRF3 protein, human; C505371:MAVS protein, human; C532857:STING1 protein, human; D000099197:STING Protein; C470409:TICAM1 protein, human; C104282:nsp1 protein, Rotavirus; C494363:CREBBP protein, human
crystal structure; innate immunity; signaling; transcription factor; type I interferon