SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages
SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages
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DOI：
10.1080/15548627.2016.1183081
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发表时间：
2016-01-01
期刊：
影响因子：
13.3
通讯作者：
Yoon, Joo-Heon
中科院分区：
文献类型：
--
作者：
Kim, Min-Ji;Bae, Soo Han;Yoon, Joo-Heon
线粒体自噬对线粒体稳态的适当调节在各种炎性疾病中是重要的。然而，线粒体自噬被激活以调节炎症反应的确切机制在很大程度上仍然未知。NLRP 3（NLR家族，含有pyrin结构域3）炎性体充当触发CASP 1（半胱天冬酶1）活化和促炎细胞因子分泌的平台。在这里，我们证明了SESN 2（sestrin 2），被称为应激诱导蛋白，通过诱导巨噬细胞中的线粒体自噬清除受损的线粒体，抑制长期的NLRP 3炎性体激活。SESN 2在响应于炎性体活化而诱导线粒体自噬中起双重作用。首先，SESN 2通过标记线粒体以供自噬机制识别来诱导线粒体启动。对于线粒体制备，SESN 2通过介导SQSTM 1（隔离体1）的聚集及其与线粒体表面上的赖氨酸63（Lys 63）连接的泛素的结合来促进线粒体的核周聚集。其次，SESN 2通过增加ULK 1（unc-51样激酶1）蛋白水平激活特异性自噬机制以降解引发的线粒体。此外，延长的LPS（脂多糖）刺激增加的SESN 2表达由巨噬细胞中的NOS 2（一氧化氮合酶2，诱导型）介导的NO（一氧化氮）介导。因此，Sesn 2缺陷型小鼠表现出有缺陷的线粒体自噬，这导致炎性小体的过度活化和2种不同脓毒症模型中死亡率的增加。我们的研究结果定义了一个独特的调节机制，线粒体自噬激活免疫稳态，保护主机从败血症。
Proper regulation of mitophagy for mitochondrial homeostasis is important in various inflammatory diseases. However, the precise mechanisms by which mitophagy is activated to regulate inflammatory responses remain largely unknown. The NLRP3 (NLR family, pyrin domain containing 3) inflammasome serves as a platform that triggers the activation of CASP1 (caspase 1) and secretion of proinflammatory cytokines. Here, we demonstrate that SESN2 (sestrin 2), known as stress-inducible protein, suppresses prolonged NLRP3 inflammasome activation by clearance of damaged mitochondria through inducing mitophagy in macrophages. SESN2 plays a dual role in inducing mitophagy in response to inflammasome activation. First, SESN2 induces mitochondrial priming by marking mitochondria for recognition by the autophagic machinery. For mitochondrial preparing, SESN2 facilitates the perinuclear-clustering of mitochondria by mediating aggregation of SQSTM1 (sequestosome 1) and its binding to lysine 63 (Lys63)-linked ubiquitins on the mitochondrial surface. Second, SESN2 activates the specific autophagic machinery for degradation of primed mitochondria via an increase of ULK1 (unc-51 like kinase 1) protein levels. Moreover, increased SESN2 expression by extended LPS (lipopolysaccharide) stimulation is mediated by NOS2 (nitric oxide synthase 2, inducible)-mediated NO (nitric oxide) in macrophages. Thus, Sesn2-deficient mice displayed defective mitophagy, which resulted in hyperactivation of inflammasomes and increased mortality in 2 different sepsis models. Our findings define a unique regulatory mechanism of mitophagy activation for immunological homeostasis that protects the host from sepsis.