CAML regulates Bim-dependent thymocyte death

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 (ER) protein 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.

Calcium-Modulating Cyclophilin Ligand Is Essential for the Survival of Activated T Cells and for Adaptive Immunity

“…Previous studies of CAML focused on its role in T cell development (12,14). In this study, we have identified a critical role of CAML in mature, peripheral T cells, specifically in the regulation of cell division and activation-induced cell death.…”

“…CAML was further demonstrated to be critical for epidermal growth factor receptor trafficking, and was found to be an important regulator of chromosome segregation in mouse embryonic fibroblasts during mitosis (10,11). Subsequent studies also showed CAML to be required for development of thymocytes and follicular B cells (12,13). However, these studies were unable to distinguish between developmental and mature functional roles for CAML because of the experimental models used, in which development of the tissues was potentially perturbed by early conditional loss of the Caml gene.…”

Identification of NCF2/p67phox as a novel p53 target gene

“…[65][66][67][68][69] However, it is now accepted that ROS may have an important role in regulating signal transduction pathways, gene expression and differentiation, although the molecular mechanisms upstream and downstream ROS generation are not fully understood. [70][71][72][73][74][75] The main nonmitochondrial sources of ROS are the NADPH oxidases, which are membrane-associated multi-protein complexes, of which NFC2/p67phox is an essential and crucial component, which produce superoxide.…”

“…22,23,28 ROS are even generated downstream of p53 and p53 family members, p63 and p73, most likely by the transcriptional modulation of genes that regulate the cellular redox state and that directly contribute to p53/p63/p73-mediated cell death. [31][32][33][34][35][36] To maintain the cellular redox state, ROS levels need to be tightly line-specific, we performed the same experiment in HaCat cell line. HaCat cells were transiently transfected to obtain NCF2 silencing.…”

Molecular cloning, expression, and characterization of cyclophilin A from Clonorchis sinensis

“…Ordinarily, the heavier the worm load, the greater the CsCyPA release and the stronger the antibodies response. The negative correlation probably explained by the released CsCyPA reduced the free antibodies by forming immunocomplexes (Ana et al 1998)or by downregulating antibodies response through inducing immune cells apoptosis (Edgar et al 2010).…”