Sustained activation of mTORC1 in macrophages increases AMPKα-dependent autophagy to maintain cellular homeostasis

Hongjie Pan, Xiao Ping Zhong, Sunhee Lee

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Background: The mechanistic target of rapamycin complex 1 (mTORC1) is a well-conserved serine/threonine protein kinase that controls autophagy as well as many other processes such as protein synthesis, cell growth, and metabolism. The activity of mTORC1 is stringently and negatively controlled by the tuberous sclerosis proteins 1 and 2 complex (TSC1/2). Results: In contrast to the previous studies using Tsc1 knockout mouse embryonic fibroblasts (MEF) cells, we demonstrated evidence that TSC1 deficient macrophages exhibited enhanced basal and mycobacterial infection-induced autophagy via AMPKα-dependent phosphorylation of ULK1 (Ser555). These effects were concomitant with constitutive activation of mTORC1 and can be reversed by addition of amino acids or rapamycin, and by the knockdown of the regulatory-associated protein of mTOR, Raptor. In addition, increased autophagy in TSC1 deficient macrophages resulted in suppression of inflammation during mycobacterial infection, which was reversed upon amino acid treatment of the TSC1 deficient macrophages. We further demonstrated that TSC1 conditional knockout mice infected with Mycobacterium tuberculosis, the causative agent of tuberculosis, resulted in less bacterial burden and a comparable level of inflammation when compared to wild type mice. Conclusions: Our data revealed that sustained activation of mTORC1 due to defects in TSC1 promotes AMPKα-dependent autophagic flux to maintain cellular homeostasis.

Original languageEnglish (US)
Article number14
JournalBMC Biochemistry
Volume17
Issue number1
DOIs
StatePublished - Jul 7 2016
Externally publishedYes

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Keywords

  • AMP-activated protein kinase (AMPK)
  • Autophagy
  • Macrophages
  • Mechanistic target of rapamycin (mTOR)
  • Mycobacterium tuberculosis
  • Tuberous sclerosis 1 (TSC1)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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