SIRT3 promotes antimycobacterial defenses by coordinating mitochondrial and autophagic functions
SIRT3 promotes antimycobacterial defenses by coordinating mitochondrial and autophagic functions
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DOI：
10.1080/15548627.2019.1582743
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发表时间：
2019-08-03
期刊：
影响因子：
13.3
通讯作者：
Jo, Eun-Kyeong
中科院分区：
文献类型：
--
作者：
Kim, Tae Sung;Jin, Yeung Bae;Jo, Eun-Kyeong
SIRT3（sirtuin 3）是一种线粒体蛋白脱乙酰酶，可维持呼吸功能，但其在调节先天免疫防御中的作用尚不清楚。在此，我们证明 SIRT3 协调线粒体功能和巨自噬/自噬激活，通过 PPARA（过氧化物酶体增殖物激活受体 α）促进抗分枝杆菌反应。 SIRT3 缺乏会增强炎症反应和线粒体功能障碍，导致分枝杆菌感染期间宿主防御缺陷和病理性炎症。抗体介导的多形核中性粒细胞耗竭显着增强了 Sirt3(-/-) 小鼠对分枝杆菌感染的保护作用。此外，线粒体氧化应激促进了结核分枝杆菌感染在sirt3(-/-)巨噬细胞中诱导的过度炎症。值得注意的是，SIRT3 对于增强 PPARA 至关重要，PPARA 是感染情况下线粒体稳态和自噬激活的关键调节因子。重要的是，sirt3(-/-)巨噬细胞中PPARA或TFEB（转录因子EB）的过度表达通过自噬激活恢复了抗菌活性。此外，SIRT3 的药理学激活增强了分枝杆菌感染期间的抗菌自噬和功能性线粒体库。最后，肺结核患者外周血单个核细胞中 SIRT3 和 PPARA 的水平下调，并与 TNF（肿瘤坏死因子）水平呈负相关。总的来说，这些数据表明 SIRT3 在协调线粒体和自噬功能以促进抗分枝杆菌反应方面具有以前未被认识到的功能。
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.