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

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75 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1272-1291
Number of pages20
JournalAutophagy
Volume12
Issue number8
DOIs
Publication statusPublished - 2016 Aug 2

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Kim, M. J., Bae, S. H., Ryu, J. C., Kwon, Y., Oh, J. H., Kwon, J., Moon, J. S., Kim, K., Miyawaki, A., Lee, M. G., Shin, J., Kim, Y. S., Kim, C. H., Ryter, S. W., Choi, A. M. K., Rhee, S. G., Ryu, J. H., & Yoon, J. H. (2016). SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages. Autophagy, 12(8), 1272-1291. https://doi.org/10.1080/15548627.2016.1183081