Priming of NLRP3 inflammasome activation by Msn kinase MINK1 in macrophages.
Priming of NLRP3 inflammasome activation by Msn kinase MINK1 in macrophages.
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巨噬细胞中 Msn 激酶 MINK1 引发 NLRP3 炎性体激活。
DOI：
10.1038/s41423-021-00761-1
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发表时间：
2021-10
影响因子：
24.1
通讯作者：
Lu L
中科院分区：
文献类型：
--
作者：
Zhu K;Jin X;Chi Z;Chen S;Wu S;Sloan RD;Lin X;Neculai D;Wang D;Hu H;Lu L
核巧酸结合结构域、富含亮氨酸重复序列家族、含化嘟结构域3（NLRP 3）炎性体在炎症和炎性疾病中是必需的。NLRP 3上不同位点的磷酸化差异调节炎性小体活化。NLRP 3上的Ser 725磷酸化位点在多种炎性小体激活情况下被描述，但该位点的重要性和调控尚未阐明。本研究揭示Ser 725的磷酸化是巨噬细胞中NLRP 3炎性体启动的必要步骤。我们还发现，Ser 725被畸形（Msn）/NIK-related kinase 1（MINK 1）直接磷酸化，这取决于MINK 1和NLRP 3 LRR结构域之间的直接相互作用。MINK 1缺陷减少NLRP 3激活，抑制急性脓毒症和腹膜炎小鼠模型的炎症反应。活性氧（ROS）上调MINK 1的激酶活性，随后通过NLRP 3 Ser 725磷酸化促进炎性小体引发。清除ROS抑制NLRP 3活化，并以MINK 1依赖性方式减少脓毒症和腹膜炎症状。总之，我们的研究揭示了MSN家族激酶MINK 1对NLRP 3炎性小体的直接调节，并表明MINK 1活性的调节是炎性小体相关疾病的潜在干预策略。
The nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 3 (NLRP3) inflammasome is essential in inflammation and inflammatory disorders. Phosphorylation at various sites on NLRP3 differentially regulates inflammasome activation. The Ser725 phosphorylation site on NLRP3 is depicted in multiple inflammasome activation scenarios, but the importance and regulation of this site has not been clarified. The present study revealed that the phosphorylation of Ser725 was an essential step for the priming of the NLRP3 inflammasome in macrophages. We also showed that Ser725 was directly phosphorylated by misshapen (Msn)/NIK-related kinase 1 (MINK1), depending on the direct interaction between MINK1 and the NLRP3 LRR domain. MINK1 deficiency reduced NLRP3 activation and suppressed inflammatory responses in mouse models of acute sepsis and peritonitis. Reactive oxygen species (ROS) upregulated the kinase activity of MINK1 and subsequently promoted inflammasome priming via NLRP3 Ser725 phosphorylation. Eliminating ROS suppressed NLRP3 activation and reduced sepsis and peritonitis symptoms in a MINK1-dependent manner. Altogether, our study reveals a direct regulation of the NLRP3 inflammasome by Msn family kinase MINK1 and suggests that modulation of MINK1 activity is a potential intervention strategy for inflammasome-related diseases.
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DOI：
10.1074/jbc.m110.203398
发表时间：
2011-08-05
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Carta S;Tassi S;Pettinati I;Delfino L;Dinarello CA;Rubartelli A
通讯作者：
Rubartelli A
影响因子：
32.4
作者：
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通讯作者：
Sutterwala FS
影响因子：
29.7
作者：
Davis BK;Wen H;Ting JP
通讯作者：
Ting JP
影响因子：
30.5
作者：
Baroja-Mazo, Alberto;Martin-Sanchez, Fatima;Pelegrin, Pablo
通讯作者：
Pelegrin, Pablo
影响因子：
3.5
作者：
Dan, I;Watanabe, NM;Kusumi, A
通讯作者：
Kusumi, A