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

Hongjie Pan1, Xiao-Ping Zhong2, Sunhee Lee3

  • 1Human Vaccine Institute and Department of Medicine, Duke University, Durham, NC, 27710, USA.

BMC Biochemistry
|July 9, 2016
PubMed
Abstract

Insights

Tuberous sclerosis complex 1 (TSC1) deficiency enhances autophagy in macrophages, suppressing inflammation during tuberculosis infection. This is mediated by sustained mechanistic target of rapamycin complex 1 (mTORC1) activation and AMPKα-dependent ULK1 phosphorylation.

Area of Science:

  • Cell Biology
  • Immunology
  • Molecular Biology

Background:

  • Mechanistic target of rapamycin complex 1 (mTORC1) regulates crucial cellular processes including autophagy, protein synthesis, cell growth, and metabolism.
  • The tuberous sclerosis proteins 1 and 2 complex (TSC1/2) is a key negative regulator of mTORC1 activity.

Purpose of the Study:

  • To investigate the role of TSC1 deficiency in macrophage autophagy and its impact on mycobacterial infection.
  • To elucidate the molecular mechanisms underlying TSC1-mediated regulation of autophagy and inflammation.

Main Methods:

  • Utilized Tsc1-deficient macrophages and TSC1 conditional knockout mice.
  • Assessed autophagy levels via AMPKα-dependent phosphorylation of ULK1 (Ser555).
  • Analyzed inflammation and bacterial burden following Mycobacterium tuberculosis infection.

Main Results:

  • TSC1-deficient macrophages displayed enhanced basal and infection-induced autophagy, linked to constitutive mTORC1 activation.
  • Increased autophagy in TSC1-deficient macrophages suppressed inflammation during infection, an effect reversed by amino acid treatment.
  • TSC1 conditional knockout mice showed reduced bacterial burden after M. tuberculosis infection.

Conclusions:

  • Sustained mTORC1 activation due to TSC1 defects promotes AMPKα-dependent autophagic flux, crucial for maintaining cellular homeostasis.
  • Targeting TSC1-mediated pathways may offer therapeutic strategies for tuberculosis by modulating autophagy and inflammation.
Keywords:
AMP-activated protein kinase (AMPK)AutophagyMacrophagesMechanistic target of rapamycin (mTOR)Mycobacterium tuberculosisTuberous sclerosis 1 (TSC1)

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