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

 Min-Ji Kim  ;  Soo Han Bae  ;  Jae-Chan Ryu  ;  Younghee Kwon  ;  Ji-Hwan Oh  ;  Jeongho Kwon  ;  Jong-Seok Moon  ;  Kyubo Kim  ;  Atsushi Miyawaki  ;  Min Goo Lee  ;  Jaekyoon Shin  ;  Young Sam Kim  ;  Chang-Hoon Kim  ;  Stefan W. Ryter  ;  Augustine M. K. Choi  ;  Sue Goo Rhee  ;  Ji-Hwan Ryu  ;  Joo-Heon Yoon 
 AUTOPHAGY, Vol.12(8) : 1272-1291, 2016 
Journal Title
Issue Date
Animals ; Autophagy* ; Autophagy-Related Protein-1 Homolog/metabolism ; Caspase 1/metabolism ; Enzyme Activation ; Humans ; Inflammasomes/metabolism ; Inflammation ; Interleukin-18/blood ; Interleukin-1beta/blood ; Intracellular Signaling Peptides and Proteins/metabolism ; Leukocytes, Mononuclear/cytology ; Lysine/chemistry ; Macrophages/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/metabolism* ; Mitochondrial Degradation ; Monocytes/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Nuclear Proteins/metabolism* ; Reactive Oxygen Species/metabolism ; Shock, Septic/metabolism*
NLRP3 inflammasome ; SESN2 ; autophagy ; mitochondrial priming ; mitophagy ; sepsis
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.
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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
Yonsei Authors
Kim, Young Sam(김영삼) ORCID logo https://orcid.org/0000-0001-9656-8482
Kim, Chang Hoon(김창훈) ORCID logo https://orcid.org/0000-0003-1238-6396
Ryu, Jae Chan(류재찬)
Bae, Soo Han(배수한) ORCID logo https://orcid.org/0000-0002-8007-2906
Ryu, Ji Hwan(유지환)
Yoon, Joo Heon(윤주헌)
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
Rhee, Sue Goo(이서구)
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