title: T cell receptor-dependent activation of mTOR signaling in T cells is mediated by Carma1 and MALT1, but not Bcl10.
abstract: Signaling to the mechanistic target of rapamycin (mTOR) regulates diverse cellular processes, including protein translation, cellular proliferation, metabolism, and autophagy. Most models place Akt upstream of the mTOR complex, mTORC1; however, in T cells, Akt may not be necessary for mTORC1 activation. We found that the adaptor protein Carma1 [caspase recruitment domain (CARD)-containing membrane-associated protein 1] and at least one of its associated proteins, the paracaspase MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1), were required for optimal activation of mTOR in T cells in response to stimulation of the T cell receptor (TCR) and the co-receptor CD28. However, Bcl10, which binds to Carma1 and MALT1 to form a complex that mediates signals from the TCR to the transcription factor NF-κB (nuclear factor κB), was not required. The catalytic activity of MALT1 was required for the proliferation of stimulated CD4+ T cells, but not for early TCR-dependent activation events. Consistent with an effect on mTOR, MALT1 activity was required for the increased metabolic flux in activated CD4+ T cells. Together, our data suggest that Carma1 and MALT1 play previously unappreciated roles in the activation of mTOR signaling in T cells after engagement of the TCR.
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Graduate Program in Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Kristia S
authors.initials: KS
authors.lastname: Hamilton
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Graduate Program in Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Binh
authors.initials: B
authors.lastname: Phong
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Corey
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Departments of Pediatrics and Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Balachandra
authors.initials: B
authors.lastname: Gorentla
authors.affiliation: Departments of Pediatrics and Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Sruti
authors.initials: S
authors.lastname: Shiva
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. lkane@pitt.edu.
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Kane
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D020169:Caspases / Q000276:immunology / Q000378:metabolism*; D049109:Cell Proliferation / Q000502:physiology; D051379:Mice; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009363:Neoplasm Proteins / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C488088:Bcl10 protein, mouse; D053468:CARD Signaling Adaptor Proteins; C496467:Card11 protein, mouse; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein