1. CAML regulates Bim-dependent thymocyte death
- Author
-
Andreas Strasser, Lonn D. Lindquist, Richard J. Bram, Contessa E. Edgar, and David L. McKean
- Subjects
T-Lymphocytes ,medicine.medical_treatment ,Apoptosis ,Biology ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Proto-Oncogene Proteins ,medicine ,Animals ,Cytotoxic T cell ,fas Receptor ,CAML: Calcium modulating cyclophilin ligand ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,Etoposide ,030304 developmental biology ,computer.programming_language ,0303 health sciences ,Bcl-2-Like Protein 11 ,Caml ,ROS: reactive oxygen species ,Endoplasmic reticulum ,Bcl-2 family ,Membrane Proteins ,Bim: Bcl-2 interacting mediator of cell death ,Cell Biology ,Fas receptor ,Cell biology ,Thymocyte ,Cytokine ,030220 oncology & carcinogenesis ,Tumor Suppressor Protein p53 ,Apoptosis Regulatory Proteins ,Reactive Oxygen Species ,computer - Abstract
Appropriate control of apoptosis during T lymphocyte differentiation is critical for destruction of T cells bearing potentially autoreactive or useless immuno-receptors and for survival of those T cells bearing antigen receptors that may recognize foreign proteins. Despite the well-established importance of thymocyte survival, the exact signals regulating thymocyte apoptosis have not been fully elucidated. Here, we show that thymocytes lacking the endoplasmic reticulum protein calcium-modulating cyclophilin ligand (CAML) failed to undergo normal T-cell development and exhibited dramatically increased rates of apoptosis. In vitro, CAML-deficient thymocytes accumulated high levels of reactive oxygen species (ROS) and underwent abnormally accelerated death in response to several cytotoxic stimuli, including treatment with etoposide, cytokine deprivation, or Fas ligation. Although neither p53 deletion nor loss of Fas rescued the survival and continued development of CAML-deficient thymocytes, removal of the pro-apoptotic BH3-only Bcl-2 family member Bim significantly restored their survival. This work reveals CAML to be a critically important regulator of ROS- and Bim-dependent thymocyte death.
- Published
- 2010