The VDAC2-BAK Rheostat Controls Thymocyte Survival

Sci. Signal., 25 August 2009
Vol. 2, Issue 85, p. ra48
DOI: 10.1126/scisignal.2000274

The VDAC2-BAK Rheostat Controls Thymocyte Survival

  1. Decheng Ren1,
  2. Hyungjin Kim1,
  3. Ho-Chou Tu1,
  4. Todd D. Westergard1,
  5. Jill K. Fisher2,
  6. Jeff A. Rubens2,
  7. Stanley J. Korsmeyer2,*,
  8. James J.-D. Hsieh1, and
  9. Emily H.-Y. Cheng1,3,
  1. 1Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
  2. 2Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  3. 3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  1. To whom correspondence should be addressed. E-mail: echeng{at}dom.wustl.edu
  • * Deceased.

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.

Citation:

D. Ren, H. Kim, H.-C. Tu, T. D. Westergard, J. K. Fisher, J. A. Rubens, S. J. Korsmeyer, J. J. Hsieh, and E. H. Cheng, The VDAC2-BAK Rheostat Controls Thymocyte Survival. Sci. Signal. 2, ra48 (2009).

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J Biol Chem 285, 36876-36883 (19 November 2010)

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