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.
Siqi Liu  1 ,  Xin Cai  1 ,  Jiaxi Wu  1 ,  Qian Cong  2 ,  Xiang Chen  3 ,  Tuo Li  1 ,  Fenghe Du  3 ,  Junyao Ren  1 ,  You-Tong Wu  1 ,  Nick V Grishin  4 ,  Zhijian J Chen  5
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. [email protected].
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.