title: X-linked mental retardation gene CUL4B targets ubiquitylation of H3K4 methyltransferase component WDR5 and regulates neuronal gene expression.
abstract: CUL4B, encoding a scaffold protein for the assembly of Cullin4B-Ring ubiquitin ligase (CRL4B) complexes, is frequently mutated in X-linked mental retardation (XLMR) patients. Here, we show that CUL4B, but not its paralog, CUL4A, targets WDR5, a core subunit of histone H3 lysine 4 (H3K4) methyltransferase complexes, for ubiquitylation and degradation in the nucleus. Knocking down CUL4B increases WDR5 and trimethylated H3K4 (H3K4me3) on the neuronal gene promoters and induces their expression. Furthermore, CUL4B depletion suppresses neurite outgrowth of PC12 neuroendocrine cells, which can be rescued by codepletion of WDR5. XLMR-linked mutations destabilize CUL4B and impair its ability to support neurite outgrowth of PC12 cells. Our results identify WDR5 as a critical substrate of CUL4B in regulating neuronal gene expression and suggest epigenetic change as a common pathogenic mechanism for CUL4B-associated XLMR.
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Yue
authors.initials: Y
authors.lastname: Xiong
mesh_terms: D000818:Animals; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D050172:Genes, X-Linked; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008958:Models, Molecular; D020932:Nerve Growth Factor / Q000378:metabolism / Q000502:physiology; D016501:Neurites / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D054875:Ubiquitination
chemical_list: C517832:CUL4B protein, human; D044842:Cullin Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C502547:WDR5 protein, human; D020932:Nerve Growth Factor; D011495:Histone-Lysine N-Methyltransferase