The VDAC2-BAK rheostat controls thymocyte survival.
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.
Ren
Decheng
D
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Kim
Hyungjin
H
Tu
Ho-Chou
HC
Westergard
Todd D
TD
Fisher
Jill K
JK
Rubens
Jeff A
JA
Korsmeyer
Stanley J
SJ
Hsieh
James J-D
JJ
Cheng
Emily H-Y
EH
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
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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