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SIRT3 promotes antimycobacterial defenses by coordinating mitochondrial and autophagic functions

Title
SIRT3 promotes antimycobacterial defenses by coordinating mitochondrial and autophagic functions
Authors
Kim T.S.Jin Y.B.Kim Y.S.Kim S.Kim J.K.Lee H.-M.Suh H.-W.Choe J.H.Kim Y.J.Koo B.-S.Kim H.-N.Jung M.Lee S.-H.Kim D.-K.Chung C.Son J.-W.Min J.-J.Kim J.-M.Deng C.-X.Kim H.S.Lee S.-R.Jo E.-K.
Ewha Authors
김현석
SCOPUS Author ID
김현석scopus
Issue Date
2019
Journal Title
Autophagy
ISSN
1554-8627JCR Link
Citation
Autophagy vol. 15, no. 8, pp. 1356 - 1375
Keywords
autophagymitochondrial homeostasisMycobacterium tuberculosisPPARASIRT3
Publisher
Taylor and Francis Inc.
Indexed
SCIE; SCOPUS WOS scopus
Document Type
Article
Abstract
SIRT3 (sirtuin 3), a mitochondrial protein deacetylase, maintains respiratory function, but its role in the regulation of innate immune defense is largely unknown. Herein, we show that SIRT3 coordinates mitochondrial function and macroautophagy/autophagy activation to promote anti-mycobacterial responses through PPARA (peroxisome proliferator activated receptor alpha). SIRT3 deficiency enhanced inflammatory responses and mitochondrial dysfunction, leading to defective host defense and pathological inflammation during mycobacterial infection. Antibody-mediated depletion of polymorphonuclear neutrophils significantly increased protection against mycobacterial infection in sirt3−/- mice. In addition, mitochondrial oxidative stress promoted excessive inflammation induced by Mycobacterium tuberculosis infection in sirt3−/- macrophages. Notably, SIRT3 was essential for the enhancement of PPARA, a key regulator of mitochondrial homeostasis and autophagy activation in the context of infection. Importantly, overexpression of either PPARA or TFEB (transcription factor EB) in sirt3−/- macrophages recovered antimicrobial activity through autophagy activation. Furthermore, pharmacological activation of SIRT3 enhanced antibacterial autophagy and functional mitochondrial pools during mycobacterial infection. Finally, the levels of SIRT3 and PPARA were downregulated and inversely correlated with TNF (tumor necrosis factor) levels in peripheral blood mononuclear cells from tuberculosis patients. Collectively, these data demonstrate a previously unappreciated function of SIRT3 in orchestrating mitochondrial and autophagic functions to promote antimycobacterial responses. Abbreviations: Ab: antibody; BCG: M. bovis Bacillus Calmette–Guérin; Baf-A1: bafilomycin A1; BMDMs: bone marrow-derived macrophages; CFU: colony forming unit; CXCL5: C-X-C motif chemokine ligand 5; EGFP: enhanced green fluorescent protein; ERFP: enhanced red fluorescent protein; FOXO3: forkhead box O3; HC: healthy controls; H&E: haematoxylin and eosin; HKL: honokiol; IHC: immunohistochemistry; IL1B: interleukin 1 beta; IL6: interleukin 6; IL12B: interleukin 12B; MDMs: monocyte-derived macrophages; MMP: mitochondrial membrane potential; Mtb: Mycobacterium tuberculosis; PBMC: peripheral blood mononuclear cells; PBS: phosphate buffered saline; PMN: polymorphonuclear neutrophil; PPARA: peroxisome proliferator activated receptor alpha; ROS: reactive oxygen species; SIRT3: sirtuin 3; TB: tuberculosis; TEM: transmission electron microscopy; TFEB: transcription factor EB; TNF: tumor necrosis factor. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.
DOI
10.1080/15548627.2019.1582743
Appears in Collections:
일반대학원 > 바이오융합과학과 > Journal papers
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