Nuclear transglutaminase 2 directly regulates expression of cathepsin S in rat cortical neurons

Transglutaminase 2 ( TG 2) is a protein that modulates neuronal survival processes. Although TG 2 is primarily cytosolic, data have suggested the nuclear localization of TG 2 is strongly associated with neuronal viability. Depletion of TG 2 in neurons results in neurite retraction and loss of viability, which is likely due to a dysregulation in gene expression. To begin to understand how TG 2 regulates neuronal gene expression, chromatin immunoprecipitation was performed in neurons with TG 2 overexpression. The resulting genomic DNA was recovered and sequenced. Bioinformatics analyses revealed that a signature DNA motif was enriched in the TG 2 immunoprecipitated genomic DNA . In particular, this motif strongly mapped to a region proximate to the gene Ctss (cathepsin S). Knockdown of TG 2 resulted in a significant increase in cathepsin S expression, which preceded the loss of neuronal viability. This is the first demonstration that TG 2 directly associates with genomic DNA and regulates gene expression in neurons. Given that expression of cathepsin S is increased in neurological disease states, our data suggest that TG 2 may play a role in promoting neuron health in part by repressing the expression of cathepsin S. Overall these data provide new insights into the function of nuclear TG 2 in neurons.