Spatial control of Ca2+ signals in lymphocytes

点击翻译按钮获取中文摘要

EXCEED THE SPACE PROVIDED. I Lymphocyte activation consists of multiple intra-cellular signaling processes. This complexity allows lymphocytes to regulate their function in various ways so that their differentiation and activation are properly carried out. Impairment in this complex system could lead to malfunctioning of the immune system, such as autoimmunity, allergy, and immunodeficiency. Nuclear factor of activated T-cells (NF-AT) is regarded as one of the most important transcription factors that controls lymphocyte activation. NF-AT is activated by Ca2+/calmodulin-dependent phosphatase calcineurin (CN). The interaction between NF-AT and CN is inhibited by FK506 and Cyclosporin A, which are broadly utilized for suppression of the immune responses. Recently, several cellular and viral proteins were also determined as the inhibitors of CN/NF-AT interaction. In the preliminary study, we identify a protein Repslthat binds the lymphoid specific Src family kinase Lck and plays a critical role in NF-AT activation in lymphocytes. Repsl is highly expressed in thymocytes and other lymphoid organs. Gene knockout of Repsl in a chicken B-cell line DT-40 resulted in abolishment of NF-AT activation due to alterations in the CN independent pathway. NF-AT activation was not restored even when cells were stimulated by pharmacological agents that bypass proximal signaling events. Additionally, these cells are more susceptible to apoptosis (antigen induced cell death:AIDC) than the wildtype cells when stimulated by the antigen receptor. Reps 1 forms a stable complex with a protein called RalBP1, which is an effector for a small GTPase Ral and has GAP activity for another GTPase CDC42/Rac proteins. Expression of a dominant negative form of Ral resulted in hyper-activation of NF-AT. Moreover, antigen receptor induced cell death was significantly enhanced. Together, Ral and Repsl have opposite effects on NF-AT regulation but both are suppressive to AIDC. In this study, we will analyze the detailed mechanism of Repsl and Ral function in lymphocyte activation and death. PERFORMANCE SITE ========================================Section End===========================================