title: Autophagy promotes T-cell survival through degradation of proteins of the cell death machinery.
abstract: Autophagy is implicated in regulating cell death in activated T cells, but the underlying mechanism is unclear. Here, we show that inhibition of autophagy via Beclin 1 gene deletion in T cells leads to rampant apoptosis in these cells upon TCR stimulation. Beclin 1-deficient mice fail to mount autoreactive T-cell responses and are resistant to experimental autoimmune encephalomyelitis. Compared with Th17 cells, Th1 cells are much more susceptible to cell death upon Beclin 1 deletion. Cell death proteins are highly increased in Beclin 1-deficient T cells and inhibition of caspases and genetic deletion of Bim reverse apoptosis. In addition, p62/sequestosome 1 binds to caspase-8 but does not control levels of procaspase-8 or other cell death-related proteins. These results establish a direct role of autophagy in inhibiting the programmed cell death through degradation of apoptosis proteins in activated T cells.
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Kovacs
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.forename: Q
authors.initials: Q
authors.lastname: Yang
authors.forename: G
authors.initials: G
authors.lastname: Li
authors.forename: I G
authors.initials: IG
authors.lastname: Garcia
authors.forename: S
authors.initials: S
authors.lastname: Ju
authors.forename: D G
authors.initials: DG
authors.lastname: Roodman
authors.forename: J J
authors.initials: JJ
authors.lastname: Windle
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: B
authors.initials: B
authors.lastname: Lu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy; D000072224:Bcl-2-Like Protein 11; D000071186:Beclin-1; D053181:Caspase 8 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D006360:Heat-Shock Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D013601:T-Lymphocytes / Q000502:physiology*; D018417:Th1 Cells / Q000502:physiology; D058504:Th17 Cells / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D053181:Caspase 8; D020169:Caspases