ESAT6 inhibits autophagy flux and promotes BCG proliferation through MTOR

Biochem Biophys Res Commun. 2016 Aug 19;477(2):195-201. doi: 10.1016/j.bbrc.2016.06.042. Epub 2016 Jun 15.

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.

Keywords: Autophagy; Early secretory antigenic target 6; Lysosome; Macrophage; Mammalian target of rapamycin; Mycobacterium tuberculosis.

MeSH terms

  • Animals
  • Antigens, Bacterial / metabolism*
  • Autophagy
  • Bacterial Load / physiology
  • Bacterial Proteins / metabolism*
  • Cell Proliferation / physiology
  • Cell Survival / physiology*
  • Cells, Cultured
  • Macrophages / cytology
  • Macrophages / microbiology*
  • Macrophages / physiology*
  • Mice
  • Mycobacterium bovis / physiology*
  • RAW 264.7 Cells
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Antigens, Bacterial
  • Bacterial Proteins
  • ESAT-6 protein, Mycobacterium tuberculosis
  • TOR Serine-Threonine Kinases