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Autophagy, Published online: 23 Jun 2016 | DOI:10.1080/15548627.2016.1183081 SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages

Abstract

Min-Ji Kim^ab, Soo Han Bae^c, Jae-Chan Ryu^ab, Younghee Kwon^ab, Ji-Hwan Oh^ab, Jeongho Kwon^d, Jong-Seok Moon^ef, Kyubo Kim^g, Atsushi Miyawaki^h, Min Goo Lee^bci, Jaekyoon Shin^d, Young Sam Kim^j, Chang-Hoon Kim^kl, Stefan W. Ryter^ef, Augustine M. K. Choi^ef, Sue Goo Rheec, Ji-Hwan Ryu^bc* & Joo-Heon Yoon^abkl*^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
^c Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
^d Sungkyunkwan University School of Medicine and Samsung Biomedical Research Institute, Suwon, Korea
^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
^g Department of Otorhinolaryngology-Head and Neck Surgery, Hallym University College of Medicine, Kangdong Sacred Heart Hospital, Seoul, Korea
^h Laboratory for Cell Function Dynamics, Brain Science Institute, RIKEN, Wako, Saitama Japan
ⁱ Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea
^j Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
^k Department of Otorhinolaryngology
^l The Airway Mucus Institute, Yonsei University College of Medicine, Seoul, Korea

^*CONTACT Joo-Heon Yoon, Department of Otorhinolaryngology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, Korea 120-752; Ji-Hwan Ryu, Severance Biomedical Science Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul,
Korea 120-752.

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.

KEYWORDS : autophagy, mitochondrial priming, mitophagy, NLRP3 inflammasome, sepsis, SESN2

논문정보

형식Research article
게재일2016년 06월 (BRIC 등록일 2016-06-28)
연구진국내(교신)+국외 연구진
분야 의약학 > 분자세포의학

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