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Tyrosine Phosphorylation of NLRP3 by Lyn Suppresses NLRP3

In ammasome Activation
Guoxin Lin, Juan Tang, Hui Guo, Yun Xiao, Neetu Gupta, Na Tang and Jian Zhang
J Immunol May 1, 2017, 198 (1 Supplement) 136.2;

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Abstract

The NLRP3 in ammasome is a multi-protein complex that triggers the activation of in ammatory caspase-1
and the maturation of IL-1β and IL-18 in response to microbes and danger signals in the cytosol of host cells.
However, how the NLRP3 in ammasome is regulated is not well de ned. Here, we showed that NLRP3
undergoes tyrosine phosphorylation in macrophages upon stimulation with ATP, a NLRP3 in ammsome
stimulus, and the tyrosine phosphorylation of NLRP3 correlates with its ubiquitination. Pretreating the
macrophages with a speci c Src kinase inhibitor inhibits NLRP3 tyrosine phosphorylation and ubiquitination,
which leads to enhanced production of IL-1β. Further we found that Src family PTK Lyn phosphorylates NLRP3
at Tyr918 which facilitates its ubiquitination and proteasome-mediated degradation. Consistent with these
data, NLRP3 tyrosine phosphorylation and ubiquitination is abrogated in macrophages lacking Lyn, which
correlates with heightened-activation of NLRP3 in ammasome. Therefore, our data demonstrates that the
Lyn-mediated tyrosine phosphorylation of NLRP3 is prerequisite for its ubiquitination, thus dampening the
NLRP3 in ammasome activity.

Copyright © 2017 by The American Association of Immunologists, Inc.

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