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

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 in this paper, 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.

Authors:
 [1];  [1];  [2];  [3];  [1];  [4];  [5];  [2];  [1]
  1. Texas A & M Univ., College Station, TX (United States). Dept. of Biochemistry and Biophysics
  2. Texas A & M Univ., College Station, TX (United States). College of Medicine, Dept. of Molecular and Cellular Medicine
  3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Berkeley Center for Structural Biology, Physical Biosciences Division
  4. Cincinnati Children's Hospital Medical Center, Cincinnati, OH (United States). Center for Systems Immunology, Division of Immunobiology; Cincinnati Children's Hospital Medical Center, Cincinnati, OH (United States). Division of Infectious Diseases
  5. Cincinnati Children's Hospital Medical Center, Cincinnati, OH (United States). Center for Systems Immunology, Division of Immunobiology; Cincinnati Children's Hospital Medical Center, Cincinnati, OH (United States). Division of Infectious Diseases
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1379399
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 113; Journal Issue: 24; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; innate immunity; signaling; type I interferon; transcription factor; crystal structure

Citation Formats

Zhao, Baoyu, Shu, Chang, Gao, Xinsheng, Sankaran, Banumathi, Du, Fenglei, Shelton, Catherine L., Herr, Andrew B., Ji, Jun-Yuan, and Li, Pingwei. Structural basis for concerted recruitment and activation of IRF-3 by innate immune adaptor proteins. United States: N. p., 2016. Web. doi:10.1073/pnas.1603269113.
Zhao, Baoyu, Shu, Chang, Gao, Xinsheng, Sankaran, Banumathi, Du, Fenglei, Shelton, Catherine L., Herr, Andrew B., Ji, Jun-Yuan, & Li, Pingwei. Structural basis for concerted recruitment and activation of IRF-3 by innate immune adaptor proteins. United States. https://doi.org/10.1073/pnas.1603269113
Zhao, Baoyu, Shu, Chang, Gao, Xinsheng, Sankaran, Banumathi, Du, Fenglei, Shelton, Catherine L., Herr, Andrew B., Ji, Jun-Yuan, and Li, Pingwei. 2016. "Structural basis for concerted recruitment and activation of IRF-3 by innate immune adaptor proteins". United States. https://doi.org/10.1073/pnas.1603269113. https://www.osti.gov/servlets/purl/1379399.
@article{osti_1379399,
title = {Structural basis for concerted recruitment and activation of IRF-3 by innate immune adaptor proteins},
author = {Zhao, Baoyu and Shu, Chang and Gao, Xinsheng and Sankaran, Banumathi and Du, Fenglei and Shelton, Catherine L. and Herr, Andrew B. and Ji, Jun-Yuan and Li, Pingwei},
abstractNote = {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 in this paper, 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.},
doi = {10.1073/pnas.1603269113},
url = {https://www.osti.gov/biblio/1379399}, journal = {Proceedings of the National Academy of Sciences of the United States of America},
issn = {0027-8424},
number = 24,
volume = 113,
place = {United States},
year = {Thu Jun 02 00:00:00 EDT 2016},
month = {Thu Jun 02 00:00:00 EDT 2016}
}

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SWI2/SNF2 ATPase CHR2 remodels pri-miRNAs via Serrate to impede miRNA production
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Rotavirus NSP1 Requires Casein Kinase II-Mediated Phosphorylation for Hijacking of Cullin-RING Ligases
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Structural basis of STAT2 recognition by IRF9 reveals molecular insights into ISGF3 function
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A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1
journal, May 2019


The eukaryotic linear motif resource – 2018 update
journal, November 2017


Structural basis of STAT2 recognition by IRF9 reveals molecular insights into ISGF3 function
journal, April 2017


Rotavirus NSP1 Requires Casein Kinase II-Mediated Phosphorylation for Hijacking of Cullin-RING Ligases
journal, August 2017