Impact of the ubiquitin system on the orchestration of signal transduction during continuous TNF challenge

• Applicant: Dr. Martin Christmann
• Subject Area: Public Health, Healthcare Research, Social and Occupational Medicine ; Rheumatology ; Cell Biology
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 391096506

Tumor necrosis factor (TNF) is a master cytokine orchestrating inflammatory response in humans. It exhibits pro-inflammatory functions but is also required for a proper termination of the immune response. The coordination of TNF signaling requires various posttranslational modifications. Disturbed TNF signal perception is a hallmark of numerous human diseases, such as SIRS and Sepsis or chronic inflammatory maladies like rheumatoid arthritis or inflammatory bowel disease as well as malignant processes. Current data indicate that a prolonged challenge of monocytic cells with TNF is associated with a deranged signal transmission culminating in an aberrant termination of pro-inflammatory signals. The preliminary experiments performed in preparation of this grant proposal revealed a significant reduction of phosphorylation at serin-20 within ubiquitin after long-term TNF exposition. In addition, a permanent TNF challenge appeared to be associated with recognizable changes of the ubiquitin system. The scope of this project will be to explore the role of ubiquitin (Ub) and ubiquitinated proteins for the orchestration of the proper sequence of TNF-induced events during prolonged challenge with the cytokine. (1) Thus, we will explore the biologic function of the rarely studied phosphorylation site at serin-20 of ubiquitin in terms of TNF-mediated signaling. (2) Furthermore, we aim to investigate the change in ubiquitinated substrates along the course of a steady TNF signal. Therefore, we will enrich and identify the pool of ubiquitinated proteins at distinct time points. Finally a more comprehensive picture of the consequences of ubiquitin regulation during permanent TNF challenge will be obtained. Such a systematic analysis of ubiquitin function during TNF signal transduction may help to improve diagnosis and prognosis of inflammatory diseases as well as malignant processes and will allow the development of more subtle therapeutic strategies.

• DFG Programme: Research Grants