Quo vadis TMEM56 - Deciphering its function

• Applicant: Dr. Ralf Wiedemuth
• Subject Area: Hematology, Oncology
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 402846583

The cell membrane represents a physical barrier that separates the inside of the cell from the surroundings in order to maintain homeostasis. Consisting of fatty acids, proteins and steroids, the interaction of these constituents defines the chemical and physical properties of the cellular membrane. Therefore, the cell membrane regulates a broad variety of essential cellular processes like cell migration, cell adhesion, intracellular transport and cell signaling. The transmembrane protein 56 (TMEM56) represents a so far uncharacterized protein, which shares a unique TLC domain with ceramide synthases. These proteins synthesize ceramide, a key intermediate of the sphingolipid metabolism. In an initial screen, we observed an altered membrane composition by an increase in spingolipid species in TMEM56-depleted cells. Interestingly, loss of TMEM56 caused a significant reduced migration toward SDF1 in vivo and in vitro. In Zebrafish embryos, the diminished TMEM56 expression impaired the location of primordial germ cells resulting in severe developmental defects. Using an indirect TMEM56-tethered reporter gene expression analysis, we observed a distinct expression of TMEM56 in murine SDF1-dependent hematopoietic and erythropoietic stem cells. Based on the specific expression in erythropoetic progenitor cells, a detailed blood analysis revealed maturation defect of red blood cells in TMEM56-/- mice.Taken together, our preliminary data points out to a role of TMEM56 in regulating the lipid metabolism in hematopoietic and erythropoietic stem cells, affecting stem cell migration and red blood cell maturation.Therefore, the aim of this project proposal is a detailed characterization of the hitherto unknown protein TMEM56. In the first period, we are going to analyze the TMEM56 expression in embryos and adult animals using the TMEM56-dependent reporter gene expression, followed by determination of the intracellular localization and identification of potential interaction partners as well as functional domains. In the subsequent phase, we will investigate the influence of TMEM56 on lipid metabolism and membrane properties in erythropoiesis.

• DFG Programme: Research Grants
• Co-Investigator: Privatdozent Dr. Sebastian Brenner