title: Sustained activation of mTORC1 in macrophages increases AMPKα-dependent autophagy to maintain cellular homeostasis.
abstract: 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).
  
  
  
  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.
  
  
  
  Our data revealed that sustained activation of mTORC1 due to defects in TSC1 promotes AMPKα-dependent autophagic flux to maintain cellular homeostasis.
authors.affiliation: Human Vaccine Institute and Department of Medicine, Duke University, Durham, NC, 27710, USA.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Pan
authors.affiliation: Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Zhong
authors.affiliation: Human Vaccine Institute and Department of Medicine, Duke University, Durham, NC, 27710, USA. sunhee.lee@duke.edu.
authors.forename: Sunhee
authors.initials: S
authors.lastname: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D001854:Bone Marrow Cells / Q000166:cytology; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D053583:Interleukin-1beta / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity; D012333:RNA, Messenger / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics
chemical_list: D053583:Interleukin-1beta; D046912:Multiprotein Complexes; D012333:RNA, Messenger; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C548179:Prkaa1 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated protein kinase (AMPK); Autophagy; Macrophages; Mechanistic target of rapamycin (mTOR); Mycobacterium tuberculosis; Tuberous sclerosis 1 (TSC1)