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SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages

DC Field Value Language
dc.contributor.author김영삼-
dc.contributor.author윤주헌-
dc.contributor.author이민구-
dc.contributor.author이서구-
dc.contributor.author김창훈-
dc.contributor.author류재찬-
dc.contributor.author배수한-
dc.contributor.author유지환-
dc.date.accessioned2017-10-26T07:07:21Z-
dc.date.available2017-10-26T07:07:21Z-
dc.date.issued2016-
dc.identifier.issn1554-8627-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/151627-
dc.description.abstractProper 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.-
dc.description.statementOfResponsibilityrestriction-
dc.publisherTaylor & Francis-
dc.relation.isPartOfAUTOPHAGY-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/2.0/kr/-
dc.subject.MESHAnimals-
dc.subject.MESHAutophagy*-
dc.subject.MESHAutophagy-Related Protein-1 Homolog/metabolism-
dc.subject.MESHCaspase 1/metabolism-
dc.subject.MESHEnzyme Activation-
dc.subject.MESHHumans-
dc.subject.MESHInflammasomes/metabolism-
dc.subject.MESHInflammation-
dc.subject.MESHInterleukin-18/blood-
dc.subject.MESHInterleukin-1beta/blood-
dc.subject.MESHIntracellular Signaling Peptides and Proteins/metabolism-
dc.subject.MESHLeukocytes, Mononuclear/cytology-
dc.subject.MESHLysine/chemistry-
dc.subject.MESHMacrophages/metabolism-
dc.subject.MESHMale-
dc.subject.MESHMice-
dc.subject.MESHMice, Inbred C57BL-
dc.subject.MESHMitochondria/metabolism*-
dc.subject.MESHMitochondrial Degradation-
dc.subject.MESHMonocytes/metabolism-
dc.subject.MESHNLR Family, Pyrin Domain-Containing 3 Protein/metabolism*-
dc.subject.MESHNitric Oxide/metabolism-
dc.subject.MESHNitric Oxide Synthase Type II/metabolism-
dc.subject.MESHNuclear Proteins/metabolism*-
dc.subject.MESHReactive Oxygen Species/metabolism-
dc.subject.MESHShock, Septic/metabolism*-
dc.titleSESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages-
dc.typeArticle-
dc.publisher.locationUnited States-
dc.contributor.collegeCollege of Medicine-
dc.contributor.departmentDept. of Internal Medicine-
dc.contributor.googleauthorMin-Ji Kim-
dc.contributor.googleauthorSoo Han Bae-
dc.contributor.googleauthorJae-Chan Ryu-
dc.contributor.googleauthorYounghee Kwon-
dc.contributor.googleauthorJi-Hwan Oh-
dc.contributor.googleauthorJeongho Kwon-
dc.contributor.googleauthorJong-Seok Moon-
dc.contributor.googleauthorKyubo Kim-
dc.contributor.googleauthorAtsushi Miyawaki-
dc.contributor.googleauthorMin Goo Lee-
dc.contributor.googleauthorJaekyoon Shin-
dc.contributor.googleauthorYoung Sam Kim-
dc.contributor.googleauthorChang-Hoon Kim-
dc.contributor.googleauthorStefan W. Ryter-
dc.contributor.googleauthorAugustine M. K. Choi-
dc.contributor.googleauthorSue Goo Rhee-
dc.contributor.googleauthorJi-Hwan Ryu-
dc.contributor.googleauthorJoo-Heon Yoon-
dc.identifier.doi10.1080/15548627.2016.1183081-
dc.contributor.localIdA02604-
dc.contributor.localIdA02781-
dc.contributor.localIdA02847-
dc.contributor.localIdA01050-
dc.contributor.localIdA01329-
dc.contributor.localIdA01798-
dc.contributor.localIdA04611-
dc.contributor.localIdA00707-
dc.relation.journalcodeJ00269-
dc.identifier.eissn1554-8635-
dc.identifier.pmid27337507-
dc.identifier.urlhttp://www.tandfonline.com/doi/full/10.1080/15548627.2016.1183081-
dc.subject.keywordNLRP3 inflammasome-
dc.subject.keywordSESN2-
dc.subject.keywordautophagy-
dc.subject.keywordmitochondrial priming-
dc.subject.keywordmitophagy-
dc.subject.keywordsepsis-
dc.contributor.alternativeNameKim, Young Sam-
dc.contributor.alternativeNameYoon, Joo Heon-
dc.contributor.alternativeNameLee, Min Goo-
dc.contributor.alternativeNameRhee, Sue Goo-
dc.contributor.alternativeNameKim, Chang Hoon-
dc.contributor.alternativeNameRyu, Jae Chan-
dc.contributor.alternativeNameBae, Soo Han-
dc.contributor.alternativeNameRyu, Ji Hwan-
dc.contributor.affiliatedAuthorYoon, Joo Heon-
dc.contributor.affiliatedAuthorLee, Min Goo-
dc.contributor.affiliatedAuthorRhee, Sue Goo-
dc.contributor.affiliatedAuthorKim, Chang Hoon-
dc.contributor.affiliatedAuthorRyu, Jae Chan-
dc.contributor.affiliatedAuthorBae, Soo Han-
dc.contributor.affiliatedAuthorRyu, Ji Hwan-
dc.contributor.affiliatedAuthorKim, Young Sam-
dc.citation.volume12-
dc.citation.number8-
dc.citation.startPage1272-
dc.citation.endPage1291-
dc.identifier.bibliographicCitationAUTOPHAGY, Vol.12(8) : 1272-1291, 2016-
dc.date.modified2017-10-24-
dc.identifier.rimsid45263-
dc.type.rimsART-
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers

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