title: Regulation of T-cell survival and mitochondrial homeostasis by TSC1.
abstract: The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and metabolism. It associates with multiple proteins and forms two distinct signaling complexes, mTORC1 and mTORC2. Accumulating evidence has revealed critical roles for intact mTOR signaling during T-cell activation and responses to microbial infection. However, the importance of mTOR regulation in T cells has yet to be explored. The TSC1/TSC2 complex has been shown to inhibit mTORC1 signaling in cell line models. We show here that deletion of TSC1 in the murine T-cell lineage results in a dramatic reduction of the peripheral T-cell pool, correlating with increased cell death. While mTORC1 is constitutively activated, mTORC2 signaling, reflected by Akt phosphorylation and activity, is decreased in TSC1-deficient T cells. Furthermore, TSC1-deficient T cells contain elevated reactive oxygen species (ROS) and exhibit decreased mitochondrial content and membrane potential, which is correlated with the activation of the intrinsic death pathway. Overall, our results demonstrate that TSC1 differentially regulates mTORC1 and mTORC2 activity, promotes T-cell survival, and is critical for normal mitochondrial homeostasis in T cells.
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: O'Brien
authors.forename: Balachandra K
authors.initials: BK
authors.lastname: Gorentla
authors.forename: Danli
authors.initials: D
authors.lastname: Xie
authors.forename: Sruti
authors.initials: S
authors.lastname: Srivatsan
authors.forename: Ian X
authors.initials: IX
authors.lastname: McLeod
authors.forename: You-Wen
authors.initials: YW
authors.lastname: He
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Zhong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002460:Cell Line; D002469:Cell Separation; D002470:Cell Survival / Q000276:immunology; D005434:Flow Cytometry; D006706:Homeostasis / Q000276:immunology*; D015151:Immunoblotting; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000276:immunology* / Q000378:metabolism; D046912:Multiprotein Complexes; D011506:Proteins / Q000276:immunology / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000276:immunology* / Q000378:metabolism
chemical_list: C504923:Crtc2 protein, mouse; D046912:Multiprotein Complexes; D011506:Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases