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

Author:

Stier Anna1,Gilberto Samuel1,Mohamed Weaam I1,Royall Lars N2,Helenius Jonne3,Mikicic Ivan4ORCID,Sajic Tatjana5,Beli Petra46ORCID,Müller Daniel J3ORCID,Jessberger Sebastian2ORCID,Peter Matthias1ORCID

Affiliation:

1. Institute of Biochemistry ETH Zurich Zurich Switzerland

2. Brain Research Institute University of Zurich Zurich Switzerland

3. Department of Biosystems Science and Engineering ETH Zurich Basel Switzerland

4. Institute of Molecular Biology Mainz Germany

5. Institute of Molecular Systems Biology ETH Zürich Zürich Switzerland

6. Institute of Developmental Biology and Neurobiology (IDN) Johannes Gutenberg University Mainz Germany

Abstract

AbstractThe 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.

Funder

Boehringer Ingelheim Fonds

Eidgenössische Technische Hochschule Zürich

Krebsliga Schweiz

Stavros Niarchos Foundation

Publisher

Springer Science and Business Media LLC

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,Molecular Biology,General Neuroscience

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