Project Description
The central question we are addressing in the lab is how membrane proteins that are either damaged or not needed by the cell are removed without affecting other proteins and the overall integrity of cellular organelles. Within this context, our main focus is to analyze how intramembrane proteases and their catalytically inactive homologues target selected membrane protein for degradation by the ubiquitin proteasome system. In earlier work we have identified and characterized two non-canonical arms of the endoplasmic reticulum (ER) associated protein degradation (ERAD) machinery. Also, we identified a link between the mitochondrial rhomboid protease PARL and mitophagy (see http://www.zmbh.uni-heidelberg.de/lemberg for more information). In this PhD project we aim to define the physiological function of the Presenilin-type intramembrane proteases SPP and to decipher its molecular mechanisms that link proteolysis to regulation of protein activity at the level of the ER. By combining quantitative organelle proteomics with CRISPR/Cas9-mediated gene editing, membrane biochemistry and classical cell biology, we plan to address the following key questions: 1.) Which proteins are cleaved by SPP? 2.) What is the physiological function of SPP in proteostasis control? 3.) How is the activity of SPP controlled?
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