Mst1 shuts off cytosolic antiviral defense through IRF3 phosphorylation.

Abstract:

:Cytosolic RNA/DNA sensing elicits primary defense against viral pathogens. Interferon regulatory factor 3 (IRF3), a key signal mediator/transcriptional factor of the antiviral-sensing pathway, is indispensible for interferon production and antiviral defense. However, how the status of IRF3 activation is controlled remains elusive. Through a functional screen of the human kinome, we 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 Thr75 and Thr253. This Mst1-mediated phosphorylation abolished activated IRF3 homodimerization, 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.

journal_name

Genes Dev

journal_title

Genes & development

authors

Meng F,Zhou R,Wu S,Zhang Q,Jin Q,Zhou Y,Plouffe SW,Liu S,Song H,Xia Z,Zhao B,Ye S,Feng XH,Guan KL,Zou J,Xu P

doi

10.1101/gad.277533.116

subject

Has Abstract

pub_date

2016-05-01 00:00:00

pages

1086-100

issue

9

eissn

0890-9369

issn

1549-5477

pii

gad.277533.116

journal_volume

30

pub_type

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