title: SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages.
abstract: 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.
authors.affiliation: a Research Center for Natural Human Defense System , Yonsei University College of Medicine , Seoul , Korea.|b Brain Korea 21 PLUS Project for Medical Science , Yonsei University College of Medicine , Seoul , Korea.
authors.forename: Min-Ji
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: c Severance Biomedical Science Institute, Yonsei University College of Medicine , Seoul , Korea.
authors.forename: Soo Han
authors.initials: SH
authors.lastname: Bae
authors.affiliation: a Research Center for Natural Human Defense System , Yonsei University College of Medicine , Seoul , Korea.|b Brain Korea 21 PLUS Project for Medical Science , Yonsei University College of Medicine , Seoul , Korea.
authors.forename: Jae-Chan
authors.initials: JC
authors.lastname: Ryu
authors.affiliation: a Research Center for Natural Human Defense System , Yonsei University College of Medicine , Seoul , Korea.|b Brain Korea 21 PLUS Project for Medical Science , Yonsei University College of Medicine , Seoul , Korea.
authors.forename: Younghee
authors.initials: Y
authors.lastname: Kwon
authors.affiliation: a Research Center for Natural Human Defense System , Yonsei University College of Medicine , Seoul , Korea.|b Brain Korea 21 PLUS Project for Medical Science , Yonsei University College of Medicine , Seoul , Korea.
authors.forename: Ji-Hwan
authors.initials: JH
authors.lastname: Oh
authors.affiliation: d Sungkyunkwan University School of Medicine and Samsung Biomedical Research Institute , Suwon , Korea.
authors.forename: Jeongho
authors.initials: J
authors.lastname: Kwon
authors.affiliation: e Joan and Sanford I. Weill Department of Medicine , Weill Cornell Medical College and New York-Presbyterian Hospital , New York , NY USA.|f Division of Pulmonary and Critical Care Medicine , Weill Cornell Medical College , New York , NY USA.
authors.forename: Jong-Seok
authors.initials: JS
authors.lastname: Moon
authors.affiliation: g Department of Otorhinolaryngology-Head and Neck Surgery , Hallym University College of Medicine, Kangdong Sacred Heart Hospital , Seoul , Korea.
authors.forename: Kyubo
authors.initials: K
authors.lastname: Kim
authors.affiliation: h Laboratory for Cell Function Dynamics , Brain Science Institute, RIKEN , Wako, Saitama Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miyawaki
authors.affiliation: b Brain Korea 21 PLUS Project for Medical Science , Yonsei University College of Medicine , Seoul , Korea.|c Severance Biomedical Science Institute, Yonsei University College of Medicine , Seoul , Korea.|i Department of Pharmacology , Yonsei University College of Medicine , Seoul , Korea.
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
authors.affiliation: d Sungkyunkwan University School of Medicine and Samsung Biomedical Research Institute , Suwon , Korea.
authors.forename: Jaekyoon
authors.initials: J
authors.lastname: Shin
authors.affiliation: j Department of Internal Medicine , Yonsei University College of Medicine , Seoul , Korea.
authors.forename: Young Sam
authors.initials: YS
authors.lastname: Kim
authors.affiliation: k Department of Otorhinolaryngology.|l The Airway Mucus Institute, Yonsei University College of Medicine , Seoul , Korea.
authors.forename: Chang-Hoon
authors.initials: CH
authors.lastname: Kim
authors.affiliation: e Joan and Sanford I. Weill Department of Medicine , Weill Cornell Medical College and New York-Presbyterian Hospital , New York , NY USA.|f Division of Pulmonary and Critical Care Medicine , Weill Cornell Medical College , New York , NY USA.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.affiliation: e Joan and Sanford I. Weill Department of Medicine , Weill Cornell Medical College and New York-Presbyterian Hospital , New York , NY USA.|f Division of Pulmonary and Critical Care Medicine , Weill Cornell Medical College , New York , NY USA.
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
authors.affiliation: c Severance Biomedical Science Institute, Yonsei University College of Medicine , Seoul , Korea.
authors.forename: Sue Goo
authors.initials: SG
authors.lastname: Rhee
authors.affiliation: b Brain Korea 21 PLUS Project for Medical Science , Yonsei University College of Medicine , Seoul , Korea.|c Severance Biomedical Science Institute, Yonsei University College of Medicine , Seoul , Korea.
authors.forename: Ji-Hwan
authors.initials: JH
authors.lastname: Ryu
authors.affiliation: a Research Center for Natural Human Defense System , Yonsei University College of Medicine , Seoul , Korea.|b Brain Korea 21 PLUS Project for Medical Science , Yonsei University College of Medicine , Seoul , Korea.|k Department of Otorhinolaryngology.|l The Airway Mucus Institute, Yonsei University College of Medicine , Seoul , Korea.
authors.forename: Joo-Heon
authors.initials: JH
authors.lastname: Yoon
mesh_terms: D000818:Animals; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D007249:Inflammation; D020382:Interleukin-18 / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008239:Lysine / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D063306:Mitophagy; D009000:Monocytes / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010544:Peroxidases; D017382:Reactive Oxygen Species / Q000378:metabolism; D012772:Shock, Septic / Q000378:metabolism*; D000084622:Sestrins
chemical_list: D000071189:Autophagy-Related Protein-1 Homolog; D020170:Caspase 1; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D008239:Lysine; 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; C508585:IL1B protein, human; C492716:Nlrp3 protein, mouse; C529380:Sesn2 protein, mouse; D000084622:Sestrins; C496317:Nos2 protein, mouse; C484754:ULK1 protein, human
keywords: NLRP3 inflammasome; SESN2; autophagy; mitochondrial priming; mitophagy; sepsis