Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation

Science. 2015 Mar 13;347(6227):aaa2630. doi: 10.1126/science.aaa2630. Epub 2015 Jan 29.

Authors

Siqi Liu¹, Xin Cai¹, Jiaxi Wu¹, Qian Cong², Xiang Chen³, Tuo Li¹, Fenghe Du³, Junyao Ren¹, You-Tong Wu¹, Nick V Grishin⁴, Zhijian J Chen⁵

Affiliations

¹ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
² Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
³ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. Howard Hughes Medical Institute (HHMI), University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
⁴ Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. Howard Hughes Medical Institute (HHMI), University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
⁵ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. Howard Hughes Medical Institute (HHMI), University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. zhijian.chen@utsouthwestern.edu.

PMID: 25636800
DOI: 10.1126/science.aaa2630

Abstract

During virus infection, the adaptor proteins MAVS and STING transduce signals from the cytosolic nucleic acid sensors RIG-I and cGAS, respectively, to induce type I interferons (IFNs) and other antiviral molecules. Here we show that MAVS and STING harbor two conserved serine and threonine clusters that are phosphorylated by the kinases IKK and/or TBK1 in response to stimulation. Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1. We further show that TRIF, an adaptor protein in Toll-like receptor signaling, activates IRF3 through a similar phosphorylation-dependent mechanism. These results reveal that phosphorylation of innate adaptor proteins is an essential and conserved mechanism that selectively recruits IRF3 to activate the type I IFN pathway.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / chemistry
Adaptor Proteins, Signal Transducing / metabolism*
Adaptor Proteins, Vesicular Transport / chemistry
Adaptor Proteins, Vesicular Transport / metabolism*
Amino Acid Sequence
Animals
Cell Line
Humans
I-kappa B Kinase / metabolism
Interferon Regulatory Factor-3 / chemistry
Interferon Regulatory Factor-3 / metabolism*
Interferon-alpha / biosynthesis
Interferon-beta / biosynthesis
Membrane Proteins / chemistry
Membrane Proteins / metabolism*
Mice
Molecular Sequence Data
Phosphorylation
Protein Binding
Protein Multimerization
Protein Serine-Threonine Kinases / metabolism
Recombinant Proteins / metabolism
Sendai virus / physiology
Serine / metabolism
Signal Transduction
Ubiquitination
Vesiculovirus / physiology

Substances

Adaptor Proteins, Signal Transducing
Adaptor Proteins, Vesicular Transport
IRF3 protein, human
Interferon Regulatory Factor-3
Interferon-alpha
MAVS protein, human
Membrane Proteins
Recombinant Proteins
STING1 protein, human
Sting1 protein, mouse
TICAM1 protein, human
Serine
Interferon-beta
Protein Serine-Threonine Kinases
TBK1 protein, human
I-kappa B Kinase

Abstract

Publication types

MeSH terms

Substances

Grants and funding