Compartmentalization is a key principle of eukaryotic cells. Cellular organelles provide functionally distinctive compartments for diverse biochemical reactions and are highly dynamic structures that adapt to environmental challenges. These adjustments can take many forms, including changes of protein and lipid composition, biochemical activities, organelle morphology or interactions with other organelles. Chronic overexposure to nutrients represents a severe form of environmental stress resulting in extensive fat deposition and severe pertubations of cellular signaling and organelle functions in many organs. The consequent cellular dysfunction leads to associated pathologies on the organismal level, including, type2 diabetes.
An essential question with broad impact on metabolism in health and disease is how nutrient overflow and pathological increase in intracellular lipids affect the protein localization and subcellular organization in different cell types and organs and how this is regulated. We therefore combine novel proteomic and phosphoproteomic workflows to adress the question how the cellular organelles change during the progression of type2 diabetes and how the develoment of insulin resistance is correlated with changes in the subcellular organization. Using this unbiased, systematic approach we want to identfy novel factors involved in the development of type2 diabets.
Charaterization of the subcellular reorganization underlying the development of insulin resistance using organelle proteomics and phosphoproteomics.
We will perform organelle proteomics in cell lines treated with different lipid species to induce insulin resistance and different organs from in vivo models for type2 diabetes to identify changes in organelle protein composition and protein relocalizations events in type2 diabetes. We will then combine phosphoproteomics with cell biological and fluorescence microscopy based methods to study the cellular mechanism underlying the subcellular relocalizations and the regulation of the detected changes of organelle composition by signaling pathways.
We have one PhD position available for a highly motivated doctoral student with interest in cell biology, proteomics and bioinformatics.
Keywords: organelles, lipid droplets, proteomics, signaling
Krahmer, N.; Najafi, B.; Schueder, F.; Quagliarini, F.; Salinas, F.; Cox J.; Uhlenhaut, N.-H.; Walther, T.C.; Jungmann, R.; Zeigerer, A.; Borner, G.H.H.; Mann, M. Organellar proteomics and phospho-proteomics reveal subcellular reorganization in diet-induced hepatic steatosis. Developmental Cell (under revision).
Krahmer, N.; Hilger, M.; Kory, N.; Wilfling, F.; Stoehr, G.; Mann, M.; Farese, R. V., Jr.; Walther, T. C. Protein correlation profiles identify lipid droplet proteins with high confidence. Mol Cell Proteomics 2013, 12, 1115-1126.
Krahmer, N.; Guo, Y.; Wilfling, F.; Hilger, M.; Lingrell, S.; Heger, K.; Newman, H. W.; Schmidt-Supprian, M.; Vance, D. E.; Mann, M.; Farese, R. V., Jr.; Walther, T. C. Phosphatidylcholine synthesis for lipid droplet expansion is mediated by localized activation of CTP:phosphocholine cytidylyltransferase. Cell Metab 2011, 14, 504-515.