한빛사 논문
Tae Sung Kima,b,c,†, Yeung Bae Jind,†, Yi Sak Kima,b,c, Sup Kima,b,c, Jin Kyung Kima,b,c, Hye-Mi Leea, Hyun-Woo Suha,c, Jin Ho Choea,b,c, Young Jae Kima,b,c, Bon-Sang Kood, Han-Na Kimd, Mingyu Junge, Sang-Hee Leef, Don-Kyu Kimg, Chaeuk Chungh, Ji-Woong Soni, Jung-Joon Minj, Jin-Man Kime, Chu-Xia Dengk, Hyun Seok Kiml, Sang-Rae Leed,†† , and Eun-Kyeong Joa,b,††
a Department of Microbiology, Chungnam National University School of Medicine Daejeon, Korea; b Department of Medical Science, Chungnam National University School of Medicine Daejeon, Korea; c Infection Control Convergence Research Center, Chungnam National University School of Medicine Daejeon, Korea. d National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Korea; e Department of Pathology, Chungnam National University School of Medicine, Daejeon, Korea; f Institute of Molecular Biology & Genetics; Seoul National University, Seoul, Korea; g Department of Molecular Biotechnology, Chonnam National University, Gwangju, Korea; h Division of Pulmonary and Critical Care, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea; i Department of Internal Medicine, Konyang University, Daejeon, Korea; j Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju, Korea; k Faculty of Health Sciences University of Macau Macau SAR, China; l Department of Bioinspired Science, Ewha Womans University, Seoul, Korea.
† These authors contributed equally to this work
†† These correspondence contributed equally to this paper.
To whom correspondence should be addressed:
Sang-Rae Lee; National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Korea.
Eun-Kyeong Jo; Department of Microbiology, Chungnam National University School of Medicine, Daejeon 35015, Korea.
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.
Key words: SIRT3, autophagy, mitochondrial homeostasis, Mycobacterium tuberculosis, PPARA
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