skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

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

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
 [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
+ Show Author Affiliations

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.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1379399
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, Issue 24; ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)Copyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 107 works
Citation information provided by
Web of Science

References (41)

The mechanism of double-stranded DNA sensing through the cGAS-STING pathway journal December 2014
STING Specifies IRF3 Phosphorylation by TBK1 in the Cytosolic DNA Signaling Pathway journal March 2012
Cyclic GMP-AMP Containing Mixed Phosphodiester Linkages Is An Endogenous High-Affinity Ligand for STING journal July 2013
Type I Inteferon Gene Induction by the Interferon Regulatory Factor Family of Transcription Factors journal September 2006
Structural Insights into the Functions of TBK1 in Innate Antimicrobial Immunity journal July 2013
Insights into interferon regulatory factor activation from the crystal structure of dimeric IRF5 journal October 2008
Overview of the CCP 4 suite and current developments journal March 2011
Type I Interferons in Host Defense journal September 2006
Identification and Characterization of MAVS, a Mitochondrial Antiviral Signaling Protein that Activates NF-κB and IRF3 journal September 2005
Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling Pathway journal August 2003
Crystal Structure of IRF-3 in Complex with CBP journal September 2005
RIG-I-like receptors: cytoplasmic sensors for non-self RNA: RIG-I-like receptors journal August 2011
Cyclic GMP-AMP Synthase Is Activated by Double-Stranded DNA-Induced Oligomerization journal December 2013
Features and development of Coot journal March 2010
Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway journal December 2012
Rotavirus nonstructural protein 1 subverts innate immune response by inducing degradation of IFN regulatory factor 3 journal March 2005
Pattern Recognition Receptors and Inflammation journal March 2010
Structure of IRF-3 Bound to the PRDIII-I Regulatory Element of the Human Interferon-β Enhancer journal June 2007
The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling journal May 2007
Functional IRF3 deficiency in a patient with herpes simplex encephalitis journal July 2015
Interferon-Stimulated Genes: A Complex Web of Host Defenses journal March 2014
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Innate Immune Sensing and Signaling of Cytosolic Nucleic Acids journal March 2014
STING-dependent cytosolic DNA sensing pathways journal February 2014
STING is a direct innate immune sensor of cyclic di-GMP journal September 2011
Cyclic [G(2′,5′)pA(3′,5′)p] Is the Metazoan Second Messenger Produced by DNA-Activated Cyclic GMP-AMP Synthase journal May 2013
Cutting Edge: A Novel Toll/IL-1 Receptor Domain-Containing Adapter That Preferentially Activates the IFN-β Promoter in the Toll-Like Receptor Signaling journal December 2002
cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING journal May 2013
Ser386 phosphorylation of transcription factor IRF-3 induces dimerization and association with CBP/p300 without overall conformational change: IRF-3 activation by S386 phosphorylation journal July 2010
Contribution of Ser386 and Ser396 to Activation of Interferon Regulatory Factor 3 journal May 2008
Rotavirus Antagonism of the Innate Immune Response journal November 2009
Innate Recognition of Viruses journal September 2007
Crystal structure of IRF-3 reveals mechanism of autoinhibition and virus-induced phosphoactivation journal October 2003
Viral RNA detection by RIG-I-like receptors journal February 2015
Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation journal January 2015
An Atomic Model of the Interferon-β Enhanceosome journal June 2007
Interferon Regulatory Factor 3 Is Regulated by a Dual Phosphorylation-dependent Switch journal May 2007
Structure-Function Analysis of STING Activation by c[G(2′,5′)pA(3′,5′)p] and Targeting by Antiviral DMXAA journal August 2013
Cyclic GMP-AMP Is an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA journal December 2012
Rotavirus NSP1 Mediates Degradation of Interferon Regulatory Factors through Targeting of the Dimerization Domain journal July 2013
[20] Processing of X-ray diffraction data collected in oscillation mode book January 1997

Cited By (11)

SWI2/SNF2 ATPase CHR2 remodels pri-miRNAs via Serrate to impede miRNA production journal May 2018
Transcription factor dimerization activates the p300 acetyltransferase journal October 2018
Structural basis of STING binding with and phosphorylation by TBK1 journal March 2019
A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1 journal May 2019
Entirely plasmid-based reverse genetics system for rotaviruses journal January 2017
Structural basis of STAT2 recognition by IRF9 reveals molecular insights into ISGF3 function journal January 2018
The eukaryotic linear motif resource – 2018 update journal November 2017
Rotavirus NSP1 Requires Casein Kinase II-Mediated Phosphorylation for Hijacking of Cullin-RING Ligases journal August 2017
Suramin potently inhibits cGAMP synthase, cGAS, in THP1 cells to modulate IFN-β levels journal June 2018
Structural basis of STAT2 recognition by IRF9 reveals molecular insights into ISGF3 function journal April 2017
The Significance of Type-I Interferons in the Pathogenesis and Therapy of Human Immunodeficiency Virus 1 Infection journal November 2017

Similar Records

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
innate immunity
signaling
type I interferon
transcription factor
crystal structure