Role of poly ADP-ribose polymerase-1 (PARP-1) in immune function and metabolic homeostasis.

摘要

NFAT-mediated gene transcription contributes significantly to immune functions. Previous studies established that understanding the molecular basis of NFAT activation is important for the great advances in immunoregulation in transplantation surgery. For example, the immunosuppressant drug cyclosporine A inhibits calcineurin, which dephosphorylates NFAT and promotes NFAT nuclear accumulation. This thesis shows that nuclear protein poly ADP-ribose polymerase-1 (PARP-1) acts as a transcription coregulator of NFAT. PARP-1 interacts with and ADP-ribosylates NFAT in an activation-dependent manner. Genetic ablation or pharmacologic inhibition of PARP-1 reduces NFAT ADP-ribosylation. Mechanically, ADP-ribosylation increases NFAT DNA binding. Functionally, IL-2 expression was reduced in T cells isolated from Parp-1-/- null mice or upon inhibition of PARP. Parp-1-/- mice also exhibit defects in T cell anergy induction, a process regulated by calcium and NFAT signaling. Together, these results demonstrate that ADP-ribosylation catalyzed by PARP-1 provides a molecular switch that positively regulates NFAT-mediated IL-2 gene transcription. These results also imply that, similar to the immunosuppressant effect produced by the blockade of calcineurin activation by CsA, PARP-1 inhibition may also be beneficial in the modulation of immune functions.; In a second project, I investigated the role of PARP-1 in the onset of obesity and type 2 diabetes. Over activation of PARP-1 enzymatic activity is a preventable cause of pancreatic beta-cell necrosis and insulin-dependent (Type 1) diabetes mellitus in mice. Similarly, hyperglycemia-induced PARP-1 over activation is an underlying mechanism of diabetic complications. However, it is unknown if PARP-1 has any role in the onset of insulin-independent (Type 2) diabetes. I found that genetic ablation of PARP-1 is associated with increased adiposity in Parp-1-/- mice. PARP-1 deficiency also decreased insulin sensitivity and impaired glucose tolerance. Resistin level, insulin secretion and insulin signaling are similar in Parp-1 -/- and control mice. While the underlying mechanism remains elusive, these results demonstrate that PARP-1 is important for glucose and insulin homeostasis and that its deficiency may be a precursor for the onset of type 2 diabetes.