Project Details
Projekt
Deciphering the link between proteostatic control by the ubiquitin-proteasome system and ferroptosis in lymphocytes
Subject Area
Cell Biology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 549867612
Ferroptosis is as a regulated form of cell death characterized by iron-dependent lipid peroxidation and certain metabolic changes. The concomitant damage of the plasma membrane results in the release of damage associated molecular patterns (DAMPs) and immunogenic cell death (ICD) with involvement of interferons. Published data and our own preliminary results suggest that the proteostatic network of cells including the ubiquitin-proteasome system (UPS) is closely interlinked with ferroptosis, however the precise molecular mechanisms remain less well defined. In this project we will tackle the unresolved questions how the UPS-dependent proteostatic control is linked to ferroptosis and how sensing of proteotoxic stress impacts the immunogenicity of ferroptotic cell death. We will define how specific components of the UPS, such as the ubiquitin activating enzyme E1, certain E3 ligases or proteasome isoforms render cells susceptible to ferroptosis. We will further investigate proteotoxic stress responses and the involvement of their components in ferroptosis, and determine the intricate interplay between ferroptosis and proteotoxic stress-driven ICD. To address these aims we will employ a combination of pharmacological and genetic editing approaches along with the molecular knowledge acquired from patients with rare proteasomopathies and proteasome inhibition in multiple myeloma. Our approach will take advantage of our expertise in amino acid transporters as well as in proteasomal control of innate immune signaling using CRISPR/Cas9 engineered surrogate cell lines, primary T or B cells from patients with inborn errors in proteasome subunits, or pharmacological targeting of myeloma cells with proteostasis disruptors. This project will provide deeper insights into ferroptotic processes and unravel critical regulatory nodes that mediate the crosstalk between proteostasis disruption, immunogenic cell death and ferroptosis. Finally, the project has a high potential to identify novel targets for treatment of multiple myeloma or for protection of hematopoietic cells from ferroptosis-driven cell death in patients with proteasomopathy.
DFG Programme
Priority Programmes
