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.

Mycobacterium tuberculosis-triggered Hippo pathway orchestrates CXCL1/2 expression to modulate host immune responses

“…It has been known to be responsive to LPS-induced TLR4 signaling44 and has been implicated in host responses during mycobacterial infection4546 and also in the modulation of chemokines during viral and certain bacterial infections454748. Interestingly, a recent report showed that MST1/2 is capable of regulating IRF3 in response to viral infection49. However, the regulation of IRF3 activity by MST1/2 during mycobacterial infection of macrophages is not known.…”

“…Interestingly, it was found that although CXCL1 and CXCL2 were MST1/2-dependent, their expression stood exclusive of LATS1/2; indicating the process to be arbitrated through some non-canonical effectors. Indeed, MST kinases are known to regulate various transcription factors, including IRF349. IRF3 is well known for its role in defending the host against viral infection and certain bacterial infections like that with Pseudomonas aeruginosa 4859.…”

Hypothiocyanous Acid Suppresses PolyI:C-Induced Antiviral Responses by Modulating IRF3 Phosphorylation in Human Airway Epithelial Cells

“…It is thus possible that IRF3 phosphorylation at these residues inhibits dimer formation and the DNA binding activity of IRF3. In fact, it has been suggested that the phosphorylation of IRF3 at the Thr75 and Thr253 residues leads to the inhibition of DNA binding and dimer formation, respectively (Meng et al 2016). We further observed that HOSCN suppresses polyI:Cinduced apoptosis, though the mechanisms by which this occurs are still unknown.…”

“…Another candidate is mammalian sterile 20-like kinase 1 (MST1), which is known to be activated by cellular oxidative stress through distinct pathways involving thioredoxin-1 (Chae et al 2012) and peroxiredoxin-1 (Morinaka et al 2011). Recently, MST1 has been identified as a negative regulator of TBK1 during viral infection (Meng et al 2016).…”

“…Finally, we used SDS-PAGE to examine whether HOSCN exposure without polyI:C pretreatment affects the phosphorylation status of IRF3, as a recent study suggested that the phosphorylation of IRF3 at the residues other than Ser386 and Ser396 impairs its activation (Meng et al 2016).…”