title: The VDAC2-BAK rheostat controls thymocyte survival.
abstract: The proapoptotic proteins BAX and BAK constitute the mitochondrial apoptotic gateway that executes cellular demise after integrating death signals. The lethal BAK is kept in check by voltage-dependent anion channel 2 (VDAC2), a mammalian-restricted VDAC isoform. Here, we provide evidence showing a critical role for the VADC2-BAK complex in determining thymocyte survival in vivo. Genetic depletion of Vdac2 in the thymus resulted in excessive cell death and hypersensitivity to diverse death stimuli including engagement of the T cell receptor. These phenotypes were completely rescued by the concurrent deletion of Bak but not that of Bax. Thus, the VDAC2-BAK axis provides a mechanism that governs the homeostasis of thymocytes. Our study reveals a sophisticated built-in rheostat that likely fine-tunes immune competence to balance autoimmunity and immunodeficiency.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Decheng
authors.initials: D
authors.lastname: Ren
authors.forename: Hyungjin
authors.initials: H
authors.lastname: Kim
authors.forename: Ho-Chou
authors.initials: HC
authors.lastname: Tu
authors.forename: Todd D
authors.initials: TD
authors.lastname: Westergard
authors.forename: Jill K
authors.initials: JK
authors.lastname: Fisher
authors.forename: Jeff A
authors.initials: JA
authors.lastname: Rubens
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Korsmeyer
authors.forename: James J-D
authors.initials: JJ
authors.lastname: Hsieh
authors.forename: Emily H-Y
authors.initials: EH
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015551:Autoimmunity / Q000235:genetics / Q000502:physiology; D017252:CD3 Complex / Q000276:immunology; D017637:Clonal Deletion / Q000235:genetics / Q000502:physiology*; D019281:Dimerization; D005260:Female; D055786:Gene Knockout Techniques; D005838:Genotype; D017136:Ion Transport / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051336:Mitochondrial Membranes / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology*; D013950:Thymus Gland / Q000166:cytology; D050996:Voltage-Dependent Anion Channel 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D017252:CD3 Complex; C485468:Cd3e protein, mouse; C494766:Vdac2 protein, mouse; D050996:Voltage-Dependent Anion Channel 2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
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