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Tyrosine phosphorylation of NLRP3 by the Src family kinase Lyn suppresses the activity of the NLRP3 inflammasome.


ABSTRACT: In response to microbes and other danger signals, the NLRP3 inflammasome in immune cells triggers the activation of the protease caspase-1, which mediates the maturation of the inflammatory cytokine IL-1β. Here, we investigated how the NLRP3 inflammasome is regulated. We found that its activation in primary mouse macrophages induced the Src family kinase Lyn to phosphorylate NLRP3 at Tyr918, which correlated with a subsequent increase in its ubiquitination that facilitated its proteasome-mediated degradation. NLRP3 tyrosine phosphorylation and ubiquitination was abrogated in Lyn-deficient macrophages, which produced increased amounts of IL-1β. Furthermore, mice lacking Lyn were more susceptible to LPS-induced septic shock in an NLRP3-dependent manner. Our data demonstrate that Lyn-mediated tyrosine phosphorylation is a prerequisite for the ubiquitination that dampens NLRP3 inflammasome activity.

SUBMITTER: Tang J 

PROVIDER: S-EPMC8815314 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Tyrosine phosphorylation of NLRP3 by the Src family kinase Lyn suppresses the activity of the NLRP3 inflammasome.

Tang Juan J   Xiao Yizhi Y   Lin Guoxin G   Guo Hui H   Deng Han-Xiang HX   Tu Sha S   Langdon Wallace Y WY   Yang Huixiang H   Tao Lijian L   Li Yalan Y   Pope R Marshall RM   Gupta Neetu N   Zhang Jian J  

Science signaling 20211026 706


In response to microbes and other danger signals, the NLRP3 inflammasome in immune cells triggers the activation of the protease caspase-1, which mediates the maturation of the inflammatory cytokine IL-1β. Here, we investigated how the NLRP3 inflammasome is regulated. We found that its activation in primary mouse macrophages induced the Src family kinase Lyn to phosphorylate NLRP3 at Tyr<sup>918</sup>, which correlated with a subsequent increase in its ubiquitination that facilitated its proteas  ...[more]

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