On April 28,2016, Pinglong Xu laboratory published a research article in Genes & Development entitled “Mst1 shuts off cytosolic antiviral defense through IRF3 phosphorylation.”
Cytosolic RNA/DNA sensing elicits primary defense against viral pathogens. Interferon regulatory factor 3 (IRF3), a key signal mediator/transcriptional factor of antiviral sensing pathway, is indispensible for interferon production and antiviral defense. Yet, how the status of IRF3 activation is controlled remains elusive.
Through a functional screen of the human kinome, Xu laboratory found that mammalian Sterile 20-like kinase 1(Mst1), but not Mst2, profoundly inhibited cytosolic nucleic acid sensing. Mst1 associated with IRF3 and directly phosphorylated IRF3 at threonine 75 and 253. This Mst1-mediated phosphorylation abolished activated IRF3 homo-dimerization, its occupancy on chromatin and subsequent IRF3-mediated transcriptional responses. In addition, Mst1 also impeded virus-induced activation of TANK-binding kinase 1 (TBK1), further attenuating IRF3 activation. As a result, Mst1 depletion or ablation enabled an enhanced antiviral response and defense in cells and mice. Therefore, the identification of Mst1 as a novel physiological negative regulator of IRF3 activation provides mechanistic insights into innate antiviral defense and potential antiviral prevention strategies.
This research was accomplished in Life Sciences Institute (LSI) and Innovation Center of Cell Signaling Network at Zhejiang University. Ph.D. candidate Fansen Meng is the first author, and graduate students Ruyuan Zhou and Shiying Wu are 2nd and 3rd authors. Dr. Pinglong Xu is the corresponding author of this research article, and LSI at Zhejiang University is the first and corresponding affiliation. This research was supported by the MOST 973 plan (2015CB553800), NSFC Project (81472665), and the National 1000 Young Talents Program. Genes & Development is a top journal in genetics, development and molecular biology, with the IF5-year of 12.8.
Mechanism for Mst1-mediated suppression of innate antiviral immunity
Link : http://genesdev.cshlp.org/content/early/2016/04/28/gad.277533.116.abstract
