SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages.
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.
['Kim|Min-Ji|MJ|', 'Bae|Soo Han|SH|', 'Ryu|Jae-Chan|JC|', 'Kwon|Younghee|Y|', 'Oh|Ji-Hwan|JH|', 'Kwon|Jeongho|J|', 'Moon|Jong-Seok|JS|', 'Kim|Kyubo|K|', 'Miyawaki|Atsushi|A|', 'Lee|Min Goo|MG|', 'Shin|Jaekyoon|J|', 'Kim|Young Sam|YS|', 'Kim|Chang-Hoon|CH|', 'Ryter|Stefan W|SW|', 'Choi|Augustine M K|AM|', 'Rhee|Sue Goo|SG|', 'Ryu|Ji-Hwan|JH|', 'Yoon|Joo-Heon|JH|']
D000818:Animals D001343:Autophagy D000071189:Autophagy-Related Protein-1 Homolog D020170:Caspase 1 D004789:Enzyme Activation D006801:Humans D058847:Inflammasomes D007249:Inflammation D020382:Interleukin-18 D053583:Interleukin-1beta D047908:Intracellular Signaling Peptides and Proteins D007963:Leukocytes, Mononuclear D008239:Lysine D008264:Macrophages D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D008928:Mitochondria D063306:Mitophagy D009000:Monocytes D000071199:NLR Family, Pyrin Domain-Containing 3 Protein D009569:Nitric Oxide D052247:Nitric Oxide Synthase Type II D009687:Nuclear Proteins D010544:Peroxidases D017382:Reactive Oxygen Species D012772:Shock, Septic
SESN2 sepsis mitophagy NLRP3 inflammasome mitochondrial priming autophagy