Mammalian target of Rapamycin inhibition and mycobacterial survival are uncoupled in murine macrophages.
Mammalian target of Rapamycin inhibition and mycobacterial survival are uncoupled in murine macrophages.
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DOI：
10.1186/1471-2091-15-4
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发表时间：
2014-02-14
期刊：
影响因子：
--
通讯作者：
Lee S
中科院分区：
文献类型：
--
作者：
Zullo AJ;Jurcic Smith KL;Lee S
自噬是对包括分枝杆菌在内的细胞内病原体的细胞反应，并且由雷帕霉素（mTOR）的哺乳动物靶标（mTOR）的直接抑制剂诱导，所述mTOR是自噬的主要负调节剂。通过化学手段或饥饿，通过mTOR抑制的自噬诱导（mTOR依赖性自噬）导致感染细胞中的分枝杆菌杀伤。然而，我们小组以前的工作表明，分枝杆菌感染巨噬细胞自然诱导自噬和哺乳动物雷帕霉素靶蛋白（mTOR）活性（mTOR独立自噬）。在目前的工作中，我们进一步探索mTOR活性和巨噬细胞中的分枝杆菌杀伤之间的关系。虽然低浓度的mTOR抑制剂雷帕霉素、Torin 1和Torin 2可以有效地降低或阻断mTOR响应脂多糖（LPS）或分枝杆菌的活性，但需要更高浓度（10 μ M）来观察耻垢分枝杆菌的杀伤。微囊藻的生长在LC3B和ATG5缺陷型骨髓来源的巨噬细胞中，高浓度的雷帕霉素也抑制了smeglobulin，这表明非自噬机制可能有助于高剂量的杀伤。由于只有在相当高浓度的mTOR抑制剂（超过抑制mTOR所需的剂量）下才能观察到分枝杆菌的杀伤作用，因此我们假设高剂量的雷帕霉素（最常用于诱导自噬杀伤的mTOR抑制剂）可能对分枝杆菌产生直接的杀菌作用。虽然用雷帕霉素短期治疗分枝杆菌不会显著影响分枝杆菌生长，但长期暴露于雷帕霉素可能会影响选定物种的体外分枝杆菌生长。这些数据，加上我们实验室以前的工作，进一步表明mTOR抑制诱导自噬是一种人工手段，以增加分枝杆菌的杀伤和掩盖更多相关的内源性自噬生物化学，需要了解。
Autophagy is a cellular response to intracellular pathogens including mycobacteria and is induced by the direct inhibitors of mammalian target of Rapamycin (mTOR), a major negative regulator of autophagy. Autophagy induction by mTOR inhibition (mTOR dependent autophagy), through chemical means or starvation, leads to mycobacterial killing in infected cells. However, previous work by our group has shown that mycobacterial infection of macrophages naturally induces both autophagy and mammalian target of Rapamycin (mTOR) activity (mTOR independent autophagy). In the current work, we further explore the relationship between mTOR activity and mycobacterial killing in macrophages. While low concentrations of the mTOR inhibitors, Rapamycin, Torin 1, and Torin 2, can effectively reduce or block mTOR activity in response to lipopolysaccharides (LPS) or mycobacteria, higher concentrations (10 uM) are required to observe Mycobacterium smegmatis killing. The growth of M. smegmatis was also inhibited by high concentrations of Rapamycin in LC3B and ATG5 deficient bone marrow derived macrophages, suggesting that non-autophagic mechanisms might contribute to killing at high doses. Since mycobacterial killing could be observed only at fairly high concentrations of the mTOR inhibitors, exceeding doses necessary to inhibit mTOR, we hypothesized that high doses of Rapamycin, the most commonly utilized mTOR inhibitor for inducing autophagic killing, may exert a direct bactericidal effect on the mycobacteria. Although a short-term treatment of mycobacteria with Rapamycin did not substantially affect mycobacterial growth, a long-term exposure to Rapamycin could impact mycobacterial growth in vitro in select species. This data, coupled with previous work from our laboratory, further indicates that autophagy induction by mTOR inhibition is an artificial means to increase mycobacterial killing and masks more relevant endogenous autophagic biochemistry that needs to be understood.
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影响因子：
11.1
作者：
He C;Klionsky DJ
通讯作者：
Klionsky DJ
影响因子：
3.4
作者：
Knodler LA;Celli J
通讯作者：
Celli J
影响因子：
7.3
作者：
Guertin, David A.;Sabatini, David M.
通讯作者：
Sabatini, David M.
DOI：
10.1073/pnas.1210500109
发表时间：
2012-11-13
影响因子：
11.1
作者：
Castillo, Eliseo F.;Dekonenko, Alexander;Deretic, Vojo
通讯作者：
Deretic, Vojo
影响因子：
3.7
作者：
Greenstein RJ;Su L;Juste RA;Brown ST
通讯作者：
Brown ST