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.
MeSH terms
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Animals
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / pharmacology
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Apoptosis / genetics
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Apoptosis / physiology
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Autoimmunity / genetics
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Autoimmunity / physiology
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CD3 Complex / immunology
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Clonal Deletion / genetics
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Clonal Deletion / physiology*
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Dimerization
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Female
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Gene Knockout Techniques
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Genotype
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Ion Transport / genetics
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Ion Transport / physiology
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Male
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Mice
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Mice, Knockout
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Mitochondrial Membranes / physiology
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T-Lymphocytes / cytology*
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Thymus Gland / cytology
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Voltage-Dependent Anion Channel 2 / deficiency
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Voltage-Dependent Anion Channel 2 / genetics
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Voltage-Dependent Anion Channel 2 / physiology*
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bcl-2 Homologous Antagonist-Killer Protein / deficiency
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bcl-2 Homologous Antagonist-Killer Protein / genetics
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bcl-2 Homologous Antagonist-Killer Protein / physiology*
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bcl-2-Associated X Protein / physiology
Substances
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Antibodies, Monoclonal
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Bak1 protein, mouse
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Bax protein, mouse
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CD3 Complex
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Cd3e protein, mouse
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Vdac2 protein, mouse
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Voltage-Dependent Anion Channel 2
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-2-Associated X Protein