Nucleation of the destruction complex on the centrosome accelerates degradation of β-catenin and regulates Wnt signal transmission-Reference-Cited by-同舟云学术

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

Published:2022-08-29 Issue:36 Volume:119 Page:
ISSN:0027-8424
Container-title:Proceedings of the National Academy of Sciences
language:en
Short-container-title:Proc. Natl. Acad. Sci. U.S.A.

Author:

Lach Ryan S.¹^ORCID,Qiu Chongxu¹^ORCID,Kajbaf Erfan Zeyaei¹,Baxter Naomi¹^ORCID,Han Dasol²,Wang Alex¹,Lock Hannah¹^ORCID,Chirikian Orlando³,Pruitt Beth¹⁴⁵^ORCID,Wilson Maxwell Z.¹²³⁵^ORCID

Affiliation:

1. Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106

2. Neuroscience Research Institute, University of California, Santa Barbara, CA 93106

3. Biomolecular Science and Engineering, University of California, Santa Barbara, CA 93106

4. Department of Mechanical Engineering, University of California, Santa Barbara, CA 93106

5. Center for BioEngineering, University of California, Santa Barbara, CA 93106

Abstract

Wnt signal transduction is controlled by the destruction complex (DC), a condensate comprising scaffold proteins and kinases that regulate β-catenin stability. Overexpressed DC scaffolds undergo liquid–liquid phase separation (LLPS), but DC mesoscale organization at endogenous expression levels and its role in β-catenin processing were previously unknown. Here, we find that DC LLPS is nucleated by the centrosome. Through a combination of CRISPR-engineered custom fluorescent tags, finite element simulations, and optogenetic tools that allow for manipulation of DC concentration and multivalency, we find that centrosomal nucleation drives processing of β-catenin by colocalizing DC components to a single reaction crucible. Enriching GSK3β partitioning on the centrosome controls β-catenin processing and prevents Wnt-driven embryonic stem cell differentiation to mesoderm. Our findings demonstrate the role of nucleators in controlling biomolecular condensates and suggest tight integration between Wnt signal transduction and the cell cycle.

Funder

UC | University of California, Santa Barbara

HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Link

https://pnas.org/doi/pdf/10.1073/pnas.2204688119

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