A20 Functional Domains Regulate Subcellular Localization and NF-Kappa B Activation.

摘要

A20 is a structurally and functionally complex molecule that represents a central node in the immune response activation network. It is a dual ubiquitin editing molecule that is capable of altering the stability and protein-protein interactions of substrate molecules. A20 tends to remain sequestered into punctate structures in the cytoplasms of both lymphoid and non- lymphoid cells. It is a negative regulator of NF-kB activation and has been shown to modify the activity of several members of the NF-kB nsignal transduction pathway. The B-cell lymphoma-10 protein or Bcl10 is a central member of this pathway. Here we show that A20 colocalizes with overexpressed Bcl10 in HEK-293 cells and that it colocalizes with Bcl10 filaments in a stimulation dependent manner in T-lymphocytes. We also demonstrate that the last three zinc fingers of A20 are able regulate the stability of Bcl10 and that conversely, a Bcl10 interacting protein (BinCard) regulates the stability of A20. Understanding the subcellular localization and biochemical activity of A20 is an essential prerequisite for the development of therapeutic A20 modulation strategies and the identification of small-molecule compounds capable of altering A20 function. The experimental data and resulting model of the regulatory activities of A20 presented in this dissertation will serve as a starting point for further investigations into the physiological role and therapeutic potential of this important and complex molecule.