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

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.

• Authors: Siqi Liu, Xin Cai, Jiaxi Wu, Qian Cong, Xiang Chen, Tuo Li, Fenghe Du, Junyao Ren, You-Tong Wu, Nick V Grishin, Zhijian J Chen
• Journal: Science (New York, N.Y.) (Science) Vol. 347 Issue 6227 Pg. aaa2630 (Mar 13 2015) ISSN: 1095-9203 [Electronic] United States
• PMID: 25636800 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Association for the Advancement of Science.

Chemical References

• 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

Topics

• Adaptor Proteins, Signal Transducing (chemistry, metabolism)
• Adaptor Proteins, Vesicular Transport (chemistry, metabolism)
• Amino Acid Sequence
• Animals
• Cell Line
• Humans
• I-kappa B Kinase (metabolism)
• Interferon Regulatory Factor-3 (chemistry, metabolism)
• Interferon-alpha (biosynthesis)
• Interferon-beta (biosynthesis)
• Membrane Proteins (chemistry, 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)