A20 is an anti-inflammatory protein that is required for terminating responses upstream of NF-kB activation. This is highlighted by the finding that mice lacking A20 develop a systemic inflammatory disease that leads to their premature death. The mechanism whereby A20 functions in the regulation of NF-kB signaling involves its novel, dual enzymatic activity. A20 has been shown to regulate the post-translational ubiquitin modification of key signaling proteins involved in NF-kB activation. The N-terminal half of A20 functions as a deubiquitinating (DUB)enzyme, removing lysine-63 linked, signaling polyubiquitin chains. The C-terminus of A20 has E3 ubiquitin ligase activity, which adds lysine-48 linked degradative polyubiquitin chains. Thus, by removing the signaling form of ubiquitin and adding the degradative ubiquitin chain, active signaling proteins are effectively eliminated. Key mutations within either domain of A20 will diminish this activity. A genome wide scan looking at susceptibility loci for inflammatory bowel disease has identified one region on chromosome 6q that contains A20. A scan of the A20 gene revealed 7 single nucleotide polymorphisms (SNPs) in the A20 coding sequence, 4 of which are non-synonymous and result in amino acid substitutions. In addition, these SNPs reside in both of A20's important enzymatic domains. Preliminary experiments have shown that the A125V SNP disrupts the enzymatic function of A20. Therefore, the experiments in this proposal are aimed to determine 1) how the A125V SNP in A20 disrupts its DUB activity, and 2) investigate the functional response of cells containing this SNP. Future studies looking at the association of these changes in the A20 gene with autoimmune diseases, such as inflammatory bowel disease, will greatly enhance our understanding of the underlying pathophysiology of these conditions. This can lead to the development of novel therapeutics to treat these inflammatory diseases.
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| Lodolce, James P; Kolodziej, Lauren E; Rhee, Lesley et al. (2010) African-derived genetic polymorphisms in TNFAIP3 mediate risk for autoimmunity. J Immunol 184:7001-9 |
