X-Linked Mental Retardation Gene CUL4B Targets Ubiquitylation of H3K4 Methyltransferase Component WDR5 and Regulates Neuronal Gene Expression

Tadashi Nakagawa, Yue Xiong

研究成果: Article査読

81 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)381-391
ページ数11
ジャーナルMolecular Cell
43
3
DOI
出版ステータスPublished - 2011 8 5

ASJC Scopus subject areas

  • 分子生物学
  • 細胞生物学

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