Targeting thioesterases to correct loss-of-function NOD2 variants.

NOD2 was the first and to do date the most frequent gene associated with inflammatory bowel disease. The NOD2 protein functions as a sensor of bacteria by binding molecules (peptidoglycans) shed from the bacterial cell wall. The IBD mutations in NOD2 result in its inactivation or partial loss of function. In 2019 we reported that NOD2 requires the attachment of 2 fatty acids to be functional. This modification termed palmitoylation is mediated by the protein zDHHC5 and is missing from many of the mutant forms of NOD2 associated with Crohn’s disease. Palmitoylation is a reversible modification and while zDHHC5 is the “writer” that adds the modification, the “eraser” that removes it has not been identified. We believe that by blocking the eraser that we can restore function to at least some of the NOD2 mutants. Our unpublished work has identified the relevant acyl thioesterase which removes palmitate and inactivates NOD2. Through the use of chemical inhibitors we are able to rescue the function of several NOD2 mutant proteins. This proposal represents the next logical steps in our goal to characterize the relevant acyl thioesterase and to determine if any FDA approved drugs can restore function to NOD2 by inhibiting this eraser.