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Title: ESAT6 inhibits autophagy flux and promotes BCG proliferation through MTOR

Abstract

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. - Highlights: • A mechanism formore » disruping autophagy flux induced by ESAT6. • ESAT6-inhibited autophagy is MTOR-dependent. • ESAT6-boosted BCG is MTOR-dependent.« less

Authors:
 [1];  [2];  [1];  [2]; ; ; ;  [1]; ;  [3];  [1];  [2]
  1. Department of Medical Immunology, Medical School, Anhui University of Science and Technology (China)
  2. (China)
  3. Affiliated Cancer Hospital, Anhui University of Science and Technology (China)
Publication Date:
OSTI Identifier:
22606156
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 477; Journal Issue: 2; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACID PHOSPHATASE; BACILLUS; CELL PROLIFERATION; INHIBITION; LYSOSOMES; MACROPHAGES; MYCOBACTERIUM TUBERCULOSIS; VIRULENCE

Citation Formats

Dong, Hu, E-mail: austhudong@126.com, Medical Inspection Center, Anhui University of Science and Technology, Huainan, Jing, Wu, E-mail: wujing8008@126.com, Medical Inspection Center, Anhui University of Science and Technology, Huainan, Runpeng, Zhao, Xuewei, Xu, Min, Mu, Ru, Cai, Yingru, Xing, Shengfa, Ni, Rongbo, Zhang, and Medical Inspection Center, Anhui University of Science and Technology, Huainan. ESAT6 inhibits autophagy flux and promotes BCG proliferation through MTOR. United States: N. p., 2016. Web. doi:10.1016/J.BBRC.2016.06.042.
Dong, Hu, E-mail: austhudong@126.com, Medical Inspection Center, Anhui University of Science and Technology, Huainan, Jing, Wu, E-mail: wujing8008@126.com, Medical Inspection Center, Anhui University of Science and Technology, Huainan, Runpeng, Zhao, Xuewei, Xu, Min, Mu, Ru, Cai, Yingru, Xing, Shengfa, Ni, Rongbo, Zhang, & Medical Inspection Center, Anhui University of Science and Technology, Huainan. ESAT6 inhibits autophagy flux and promotes BCG proliferation through MTOR. United States. doi:10.1016/J.BBRC.2016.06.042.
Dong, Hu, E-mail: austhudong@126.com, Medical Inspection Center, Anhui University of Science and Technology, Huainan, Jing, Wu, E-mail: wujing8008@126.com, Medical Inspection Center, Anhui University of Science and Technology, Huainan, Runpeng, Zhao, Xuewei, Xu, Min, Mu, Ru, Cai, Yingru, Xing, Shengfa, Ni, Rongbo, Zhang, and Medical Inspection Center, Anhui University of Science and Technology, Huainan. Fri . "ESAT6 inhibits autophagy flux and promotes BCG proliferation through MTOR". United States. doi:10.1016/J.BBRC.2016.06.042.
@article{osti_22606156,
title = {ESAT6 inhibits autophagy flux and promotes BCG proliferation through MTOR},
author = {Dong, Hu, E-mail: austhudong@126.com and Medical Inspection Center, Anhui University of Science and Technology, Huainan and Jing, Wu, E-mail: wujing8008@126.com and Medical Inspection Center, Anhui University of Science and Technology, Huainan and Runpeng, Zhao and Xuewei, Xu and Min, Mu and Ru, Cai and Yingru, Xing and Shengfa, Ni and Rongbo, Zhang and Medical Inspection Center, Anhui University of Science and Technology, Huainan},
abstractNote = {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. - Highlights: • A mechanism for disruping autophagy flux induced by ESAT6. • ESAT6-inhibited autophagy is MTOR-dependent. • ESAT6-boosted BCG is MTOR-dependent.},
doi = {10.1016/J.BBRC.2016.06.042},
journal = {Biochemical and Biophysical Research Communications},
number = 2,
volume = 477,
place = {United States},
year = {Fri Aug 19 00:00:00 EDT 2016},
month = {Fri Aug 19 00:00:00 EDT 2016}
}