Regulation of membraneless organelles through phosphatase-DYRK kinase feedback

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.