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The CUL4B‐based E3 ubiquitin ligase regulates mitosis and brain development by recruiting phospho‐specific DCAFs


Stier, Anna; Gilberto, Samuel; Mohamed, Weaam I; Royall, Lars N; Helenius, Jonne; Mikicic, Ivan; Sajic, Tatjana; Beli, Petra; Müller, Daniel J; Jessberger, Sebastian; Peter, Matthias (2023). The CUL4B‐based E3 ubiquitin ligase regulates mitosis and brain development by recruiting phospho‐specific DCAFs. The EMBO Journal, 42(17):e112847.

Abstract

The paralogs CUL4A and CUL4B assemble cullin‐RING E3 ubiquitin ligase (CRL) complexes regulating multiple chromatin‐associated cellular functions. Although they are structurally similar, we found that the unique N‐terminal extension of CUL4B is heavily phosphorylated during mitosis, and the phosphorylation pattern is perturbed in the CUL4B‐P50L mutation causing X‐linked intellectual disability (XLID). Phenotypic characterization and mutational analysis revealed that CUL4B phosphorylation is required for efficient progression through mitosis, controlling spindle positioning and cortical tension. While CUL4B phosphorylation triggers chromatin exclusion, it promotes binding to actin regulators and to two previously unrecognized CUL4B‐specific substrate receptors (DCAFs), LIS1 and WDR1. Indeed, co‐immunoprecipitation experiments and biochemical analysis revealed that LIS1 and WDR1 interact with DDB1, and their binding is enhanced by the phosphorylated N‐terminal domain of CUL4B. Finally, a human forebrain organoid model demonstrated that CUL4B is required to develop stable ventricular structures that correlate with onset of forebrain differentiation. Together, our study uncovers previously unrecognized DCAFs relevant for mitosis and brain development that specifically bind CUL4B, but not the CUL4B‐P50L patient mutant, by a phosphorylation‐dependent mechanism.

Abstract

The paralogs CUL4A and CUL4B assemble cullin‐RING E3 ubiquitin ligase (CRL) complexes regulating multiple chromatin‐associated cellular functions. Although they are structurally similar, we found that the unique N‐terminal extension of CUL4B is heavily phosphorylated during mitosis, and the phosphorylation pattern is perturbed in the CUL4B‐P50L mutation causing X‐linked intellectual disability (XLID). Phenotypic characterization and mutational analysis revealed that CUL4B phosphorylation is required for efficient progression through mitosis, controlling spindle positioning and cortical tension. While CUL4B phosphorylation triggers chromatin exclusion, it promotes binding to actin regulators and to two previously unrecognized CUL4B‐specific substrate receptors (DCAFs), LIS1 and WDR1. Indeed, co‐immunoprecipitation experiments and biochemical analysis revealed that LIS1 and WDR1 interact with DDB1, and their binding is enhanced by the phosphorylated N‐terminal domain of CUL4B. Finally, a human forebrain organoid model demonstrated that CUL4B is required to develop stable ventricular structures that correlate with onset of forebrain differentiation. Together, our study uncovers previously unrecognized DCAFs relevant for mitosis and brain development that specifically bind CUL4B, but not the CUL4B‐P50L patient mutant, by a phosphorylation‐dependent mechanism.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Brain Research Institute
Dewey Decimal Classification:610 Medicine & health
570 Life sciences; biology
Scopus Subject Areas:Life Sciences > General Neuroscience
Life Sciences > Molecular Biology
Life Sciences > General Biochemistry, Genetics and Molecular Biology
Life Sciences > General Immunology and Microbiology
Uncontrolled Keywords:General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, Molecular Biology, General Neuroscience
Language:English
Date:4 September 2023
Deposited On:18 Jan 2024 09:25
Last Modified:11 Jul 2024 07:15
Publisher:Nature Publishing Group
ISSN:0261-4189
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.15252/embj.2022112847
PubMed ID:37365982
Project Information:
  • : FunderBoehringer Ingelheim Fonds
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  • : Project Title
  • : FunderEidgenössische Technische Hochschule Zürich
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  • : Project Title
  • : FunderKrebsliga Schweiz
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  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)