| Autor: |
Tang, Juan, Xiao, Yizhi, Lin, Guoxin, Guo, Hui, Deng, Han-Xiang, Tu, Sha, Langdon, Wallace Y., Yang, Huixiang, Tao, Lijian, Li, Yalan, Pope, R. Marshall, Gupta, Neetu, Zhang, Jian |
| Předmět: |
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| Zdroj: |
Science Signaling; 10/26/2021, Vol. 14 Issue 706, p1-13, 13p |
| Abstrakt: |
Lyn limits the inflammasome: The inflammasome is a protein complex that is central to the immune response to infection, but it also is implicated in driving inflammatory disease. Tang et al. found that the tyrosine kinase Lyn limits the activity of the inflammasome. In bone marrow–derived mouse macrophages, stimuli-induced formation of the NLRP3 inflammasome led to Lyn-mediated phosphorylation of a tyrosine residue in NLRP3 that promoted its ubiquitination and degradation. Lyn deficiency, which is associated with some autoimmune diseases, led to an enhanced inflammatory response in cells and to sepsis in mice. The findings thus identify direct inhibition of the inflammasome as another mechanism by which Lyn limits inflammation. 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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