The CUL4B-based E3 ubiquitin ligase regulates mitosis and brain development by recruiting phospho-specific DCAFs
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. Show more
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https://doi.org/10.3929/ethz-b-000621898Publication status
publishedExternal links
Journal / series
The EMBO JournalVolume
Pages / Article No.
Publisher
EMBO PressSubject
Cullin 4B; cytoskeleton regulation; mitosis; phosphorylation; ubiquitin-proteasome systemOrganisational unit
03595 - Peter, Matthias / Peter, Matthias
03870 - Müller, Daniel J. / Müller, Daniel J.
Funding
179283 - Characterizing the function and regulation of CRL4 and hGID E3-ubiquitin ligases in cell proliferation (SNF)
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