Regulation of NOD2-dependent NF-kB signaling by tumour suppressor network.
Date of Issue2011
School of Biological Sciences
DUKE-NUS Graduate Medical School SIngapore
For the past 10 years, much research has focused on understanding how NOD-like receptor (NLR) family plays a role in innate immunity. NOD2, a bona fide intracellular NLR, is an effective cystolic innate receptor that detects conserved bacterial molecular signatures within the host cytosol. Stimulation of NOD2 with bacterial ligands results in NF-kB activation. Although most studies have focused on the signaling that occurs after NOD2 activation, there are still large gaps in our understanding towards how NOD2 signaling is regulated. There may be more regulators of NOD2 signaling that have not been determined. In this study, seven genes belonging to the tumour suppressor network, mainly ATM, MDM2, WRAP53, T2BP, BBC3, NYREN18 and TP53 were examined to elucidate their role as novel regulators of NOD2-dependent NF-B signaling. Using optimised siRNA silencing assay, this study demonstrates for the first time that only ATM, MDM2, WRAP53, NYREN18 and TP53 play a positive regulatory role on NOD2 signaling such that silencing these genes mediates the attenuation of NF-B activation in HEK293T cells. Overexpression assay also reveals that among the five genes, only MDM2 and NYREN18 act downstream of kinase RIP2, a key molecule required for NF-B activation. Western blot assay also validates the finding that silencing MDM2 and NYREN18 resulted in decreased NOD2-dependent NF-B activation in a more relevant human monocytic cell line. Taken together, the data from this study provide new insights on the regulation of innate immune responses initiated by NOD2.
Final Year Project (FYP)
Nanyang Technological University