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NIH Award from the National Institute of Allergy and Infectious Diseases

Functional Analysis of Polymorphisms in the Anti-Inflammatory Protein A20

  • Principal Investigator: James Lodolce, PhD, Postdoctoral Fellow, Section Gastroenterology, Hepatology and Nutrition, Department of Medicine
  • Start Date: July 17, 2009
  • Total Award Amount: $59,402

Public Health Relevance

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.

Project Description

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.

This award is funded under the American Recovery and Reinvestment Act of 2009, NIH Award number: 1F32AI077235-01A1

James Lodolce

James Lodolce, PhD,
Postdoctoral Fellow, Section Gastroenterology, Hepatology and Nutrition, Department of Medicine