PhosphoMLO · Regulation of membraneless organelles through phosphatase-DYRK kinase feedback
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2022-09-01 → 2024-08-31
- EU contribution
- €191,149
- Participants
- 1
- Scheme
- MSCA-IF
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Results in brief
Regulation of membraneless organelles through phosphatase-DYRK kinase feedback
Biological molecules like proteins and RNAs interact within cells to perform specific functions. Some of these inter-molecular protein-RNA interactions lead to the formation of compartments that are separated from the rest of the cell. These compartments broadly function to segregate components from the rest of the cell or concentrate reaction machinery to promote specific processes. Recent research continues to reveal the presence of new compartments driven by loose interactions among disordered regions of proteins, as well as elucidate the functions of known compartments. For example, although nuclear speckles are conserved across cell types throughout the animal kingdom and dysregulation of their components occurs in human diseases including cancer and neurodegenerative disease, their exact functions are still unclear. By uncovering the modulators of nuclear speckles and other condensates in human cells, we can target their properties and observe cellular changes to gain insight into their functions. Understanding the normal regulation and function of cellular processes is crucial to developing methods to reverse disease-mediated changes. The overall objectives of the project were to 1) identify enzymatic regulators of condensates, 2) characterize the interactions between enzymatic regulators and their target condensates, and 3) define the relationships among opposing regulators.
Data: CORDIS, © European Union
Project objective
As the demographics of Europe and other developed countries shift ever older, neurodegenerative diseases involving aberrant protein aggregation grow more common but still lack effective treatment options. In healthy eukaryotic cells, the reversible weak aggregation of proteins and RNAs is necessary for the formation of condensates known as membraneless organelles. The roles of these condensates are still under investigation but may include concentrating proteins to facilitate reactions and buffering protein availability in a variety of cellular pathways. Identifying the molecular regulators of condensate assembly and maintenance is important to understand the transition from reversible to irreversible aggregation during disease and to determine potential therapeutic targets. The host lab has found that sufficient concentrations of the kinase DYRK3 trigger the dissolution of condensates, including splicing speckles, the pericentriolar matrix, and stress granules, by phosphorylating their component proteins. While in C. elegans, the serine/threonine phosphatase PP2A plays a crucial role in the assembly of membraneless organelles by dephosphorylating the substrates of the DYRK family kinase MBK-2, little is known about dephosphorylation of DYRK3 substrates in human cells or the regulation of DYRK3 activity. I hypothesize that feedback between DYRK3 and a phosphatase controls cycling of DYRK3 and its substrates between membraneless organelles and a dilute phase. I will apply interdisciplinary approaches including genetic perturbations, biochemical experiments, imaging, and mathematical modelling to address this hypothesis, in the process uncovering key regulators of condensate formation, emergent properties of feedback regulation, and a new mechanism for the regulation of phase-separated compartments.
Original text from CORDIS.
Participants
- UNIVERSITAT ZURICH · ZurichCoordinatorSwitzerland
Links
Data: CORDIS, © European Union