ESAT6 inhibits autophagy flux and promotes BCG proliferation through MTOR
ESAT6 inhibits autophagy flux and promotes BCG proliferation through MTOR
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ESAT6 通过 MTOR 抑制自噬流并促进 BCG 增殖
DOI：
10.1016/j.bbrc.2016.06.042
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发表时间：
2016-08-19
影响因子：
3.1
通讯作者：
Zhang Rongbo
中科院分区：
文献类型：
--
作者：
Hu Dong;Wu Jing;Zhang Rongbo
近年来，越来越多的研究发现致病性结核分枝杆菌（Mycobacterium tuberculosis，Mtb）抑制自噬，从而介导抗结核反应，但其机制尚不清楚。我们之前报道过Mtb的分泌性酸性磷酸酶（SapM）可以负调节自噬通量。近年来，Mtb的另一毒力因子ESAT 6（early secretory antigenic target 6）被发现参与抑制自噬，但其机制尚不清楚。在这项研究中，我们表明ESAT 6阻碍自噬通量，以促进卡介苗（BCG）增殖，并揭示了ESAT 6以雷帕霉素（MTOR）依赖的方式阻断自噬体-溶酶体融合的机制。在Raw264.7细胞和来源于小鼠腹腔（ACM）的原代巨噬细胞中，ESAT 6通过干扰自噬体-溶酶体融合来抑制自噬通量，这导致BCG负荷增加。ESAT 6对LC 3 II和SQSTM 1的降解受损与MTOR活性上调有关。首先，用Torin 1抑制MTOR消除了ESAT 6诱导的自噬阻断和溶酶体功能障碍。此外，在Raw 264.7和ACM细胞中，MTOR抑制显著抑制BCG的存活。总之，我们的研究强调了ESAT 6如何以激活MTOR的方式阻断自噬并促进BCG存活。(C)2016 Elsevier Inc. All rights reserved.
In recent years, increasing studies have found that pathogenic Mycobacterium tuberculosis (Mtb) inhibits autophagy, which mediates the anti-mycobacterial response, but the mechanism is not clear. We previously reported that secretory acid phosphatase (SapM) of Mtb can negatively regulate autophagy flux. Recently, another virulence factor of Mtb, early secretory antigenic target 6 (ESAT6), has been found to be involved in inhibiting autophagy, but the mechanism remains unclear. In this study, we show that ESAT6 hampers autophagy flux to boost bacillus Calmette-Guerin (BCG) proliferation and reveals a mechanism by which ESAT6 blocks autophagosome-lysosome fusion in a mammalian target of rapamycin (MTOR)-dependent manner. In both Raw264.7 cells and primary macrophages derived from the murine abdominal cavity (ACM), ESAT6 repressed autophagy flux by interfering with the autophagosome-lysosome fusion, which resulted in an increased load of BCG. Impaired degradation of LC3II and SQSTM1 by ESAT6 was related to the upregulated activity of MTOR. Contrarily, inhibiting MTOR with Torin1 removed the ESAT6-induced autophagy block and lysosome dysfunction. Furthermore, in both Raw264.7 and ACM cells, MTOR inhibition significantly suppressed the survival of BCG. In conclusion, our study highlights how ESAT6 blocks autophagy and promotes BCG survival in a way that activates MTOR. (C) 2016 Elsevier Inc. All rights reserved.