Nucleation of the destruction complex on the centrosome accelerates degradation of β-catenin and regulates Wnt signal transmission

Lach, R. S.; Qiu, C.; Kajbaf, E. Z.; Baxter, N. J.; Han, D.; Wang, A. Y.; Lock, H. M.; Chirikin, O.; Pruitt, B. L.; Wilson, M. Z.

doi:10.1101/2022.02.01.478717

bioRxiv · 10.1101/2022.02.01.478717

Nucleation of the destruction complex on the centrosome accelerates degradation of β-catenin and regulates Wnt signal transmission

Lach, R. S.·Qiu, C.·Kajbaf, E. Z.·Baxter, N. J.·Han, D.·Wang, A. Y.·Lock, H. M.·Chirikin, O.·Pruitt, B. L.·Wilson, M. Z.

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Abstract

Wnt signal transduction is mediated by a protein assembly called the Destruction Complex (DC) made from scaffold proteins and kinases that are essential for transducing extracellular Wnt ligand concentrations to changes in nuclear {beta}-catenin, the pathways transcriptional effector. Recently, DC scaffold proteins have been shown to undergo liquid-liquid phase separation in vivo and in vitro providing evidence for a mesoscale organization of the DC. However, the mesoscale organization of DC at endogenous expression levels and how that organization could play a role in {beta}-catenin processing is unknown. Here we find that the native mesoscale structure is a dynamic biomolecular condensate nucleated by the centrosome. Through a combination of advanced microscopy, CRISPR-engineered custom fluorescent tags, finite element simulations, and optogenetic tools, that allow for independent manipulation of the biophysical parameters that drive condensate formation, we find that a function of DC nucleation by the centrosome is to drive efficient processing of {beta}-catenin by co-localizing DC components to a single reaction hub. We demonstrate that simply increasing the concentration of a single DC kinase onto the centrosome controls {beta}-catenin processing. This simple change in localization completely alters the fate of the Wnt-driven human embryonic stem cell differentiation to mesoderm. Our findings demonstrate the role of nucleators in dynamically controlling the activities of biomolecular condensates and suggest a tight integration between cell cycle progression and Wnt signal transduction.

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Lach, R. S., Qiu, C., Kajbaf, E. Z., Baxter, N. J., Han, D., Wang, A. Y., Lock, H. M., Chirikin, O., Pruitt, B. L., Wilson, M. Z.. 2022-02-03. Nucleation of the destruction complex on the centrosome accelerates degradation of β-catenin and regulates Wnt signal transmission. https://doi.org/10.1101/2022.02.01.478717

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