Immunity
Volume 46, Issue 4, 18 April 2017, Pages 635-648
Journal home page for Immunity

Article
Tyrosine Kinase SYK Licenses MyD88 Adaptor Protein to Instigate IL-1α-Mediated Inflammatory Disease

https://doi.org/10.1016/j.immuni.2017.03.014Get rights and content
Under an Elsevier user license
open archive

Highlights

  • MyD88 is posttranscriptionally regulated by tyrosine phosphorylation

  • SYK directly phosphorylates MyD88 to induce disease in Ptpn6spin mice

  • SHP1 inhibits SYK activation to regulate MyD88 phosphorylation

  • SHP1, SYK and MyD88 interactions are central to RIPK1-TAK1-mediated inflammation

Summary

Mice carrying a hypomorphic point mutation in the Ptpn6 gene (Ptpn6spin mice) develop an inflammatory skin disease that resembles neutrophilic dermatosis in humans. Here, we demonstrated that interleukin-1α (IL-1α) signaling through IL-1R and MyD88 in both stromal and immune cells drive inflammation in Ptpn6spin mice. We further identified SYK as a critical kinase that phosphorylates MyD88, promoted MyD88-dependent signaling and mediates dermatosis in Ptpn6spin mice. Our studies further demonstrated that SHP1 encoded by Ptpn6 binds and suppresses SYK activation to inhibit MyD88 phosphorylation. Downstream of SHP1 and SYK-dependent counterregulation of MyD88 tyrosine phosphorylation, we have demonstrated that the scaffolding function of receptor interacting protein kinase 1 (RIPK1) and tumor growth factor-β activated kinase 1 (TAK1)-mediating signaling were required to spur inflammatory disease. Overall, these studies identify SHP1 and SYK crosstalk as a critical regulator of MyD88 post-translational modifications and IL-1-driven inflammation.

Keywords

SHP1
Ptpn6
SYK
IL-1α
IL-1β
MyD88
RIPK1
RIPK3
necrosis
autoinflammation
TAK1
myeloid cells
MLKL

Cited by (0)

5

These authors contributed equally

6

Lead contact