title: Chaperone-mediated autophagy regulates T cell responses through targeted degradation of negative regulators of T cell activation.
abstract: Chaperone-mediated autophagy (CMA) targets soluble proteins for lysosomal degradation. Here we found that CMA was activated in T cells in response to engagement of the T cell antigen receptor (TCR), which induced expression of the CMA-related lysosomal receptor LAMP-2A. In activated T cells, CMA targeted the ubiquitin ligase Itch and the calcineurin inhibitor RCAN1 for degradation to maintain activation-induced responses. Consequently, deletion of the gene encoding LAMP-2A in T cells caused deficient in vivo responses to immunization or infection with Listeria monocytogenes. Impaired CMA activity also occurred in T cells with age, which negatively affected their function. Restoration of LAMP-2A in T cells from old mice resulted in enhancement of activation-induced responses. Our findings define a role for CMA in regulating T cell activation through the targeted degradation of negative regulators of T cell activation.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Rut
authors.initials: R
authors.lastname: Valdor
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Enric
authors.initials: E
authors.lastname: Mocholi
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Yair
authors.initials: Y
authors.lastname: Botbol
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Guerrero-Ros
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Chandra
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Koga
authors.affiliation: 1] Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gravekamp
authors.affiliation: 1] Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Ana Maria
authors.identifier: 000000020771700X
authors.initials: AM
authors.lastname: Cuervo
authors.affiliation: 1] Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Macian
mesh_terms: D000375:Aging / Q000276:immunology; D000818:Animals; D001343:Autophagy / Q000276:immunology*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D065095:Calcineurin Inhibitors / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D000074623:Dual Oxidases; D005260:Female; D006801:Humans; D007114:Immunization; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D052119:Lysosomal-Associated Membrane Protein 2 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000276:immunology*; D009124:Muscle Proteins / Q000378:metabolism; D019255:NADPH Oxidases / Q000235:genetics; D018384:Oxidative Stress / Q000276:immunology; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D065095:Calcineurin Inhibitors; D002135:Calcium-Binding Proteins; C511512:DSCR1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D052119:Lysosomal-Associated Membrane Protein 2; D018832:Molecular Chaperones; D009124:Muscle Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011948:Receptors, Antigen, T-Cell; C484068:Tcfeb protein, mouse; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C519130:Duox1 protein, mouse; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases