PhD ceremony Mr. E. Burstein: COMMD1: a modulator of immunity and NF-κB activity

PhD ceremony: Mr. E. Burstein, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: COMMD1: a modulator of immunity and NF-κB activity

Promotor(s): prof. T.N. Wijmenga, prof. M.H. Hofker

Faculty: Medical Sciences

Inflammation is a genetically programmed cellular response to injury and pathogen invasion. The NF-κB transcription factor is a central regulator of this response and plays a critical role in immunity. As such, pathways that control its activity are intensively studied. Most of the work in the field has focused on activation steps that initiate NF-κB dependent gene expression, primarily by activation of the IKK complex downstream of various signal transduction pathways. Thereafter, homeostatic pathways that inactivate NF-κB and restore back the basal state are important to avert prolonged NF-κB responses and chronic inflammation. However, this has received less attention in the field. Over the past few years it has been appreciated that ubiquitin-mediated degradation of active, DNA-bound NF-κB subunits plays an important role in controlling pro-inflammatory gene expression. This pathway constitutes a major mechanism to restore the basal state in the NF-κB system, but the mechanism responsible for mediating and regulating NF-κB ubiquitination was not initially apparent. Here we identified a new protein called COMMD1, which shows to be important to promote the termination of NF-κB activity. In this thesis we present the mechanism by which COMMD1 regulates NF-κB activity and evaluate its role in controlling inflammation in vivo. The work gives new insights in the mechanism by which inflammation is regulated and reveals new potential targets to treat inflammatory diseases.