SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages
Authors: Chang-Hoon Kim
Min-Ji Kim
Joo-Heon Yoon
Jeongho Kwon
Soo Han Bae
Stefan W Ryter
Augustine M K Choi
Ji-Hwan Ryu
Atsushi Miyawaki
Younghee Kwon
Kyubo Kim
Jae-Chan Ryu
Young Sam Kim
Sue Goo Rhee
Jaekyoon Shin
Ji-Hwan Oh
Jong-Seok Moon
Min Goo Lee
Journal: Autophagy (2016)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: NLRP3 inflammasome; SESN2; autophagy; mitochondrial priming; mitophagy
Affiliations: 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.

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. 

Retracted: No

PubPeer comments:
 Figure 3D. Much more similar than expected for bands 3 lanes apart. https: imgur.com 7B5UPkz ,