RNF12 X-linked intellectual disability mutations disrupt E3 ligase activity and neural differentiation

Francisco Bustos, Anna Segarra Fas, Viduth K. Chaugule, Lennart Brandenburg, Emma Branigan, Rachel Toth, Thomas Macartney, Axel Knebel, Ronald Hay, Helen Walden, Greg Findlay (Lead / Corresponding author)

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Abstract

X-linked Intellectual disability (XLID) is a heterogeneous syndrome affecting mainly males. Human genetics has identified >100 XLID genes, although the molecular and developmental mechanisms underpinning this disorder remain unclear. Here, we employ an embryonic stem cell model to explore developmental functions of a recently-identified XLID gene, the RNF12/RLIM E3 ubiquitin ligase. We show that RNF12 catalytic activity is required for proper stem cell maintenance and neural differentiation, and this is disrupted by patient-associated XLID mutation. We further demonstrate that RNF12 XLID mutations specifically impair ubiquitylation of developmentallyrelevant substrates. XLID mutants disrupt distinct RNF12 functional modules, either by inactivating the catalytic RING domain or interfering with a distal regulatory region required for efficient ubiquitin transfer. Our data thereby uncover a key function for RNF12 E3 ubiquitin ligase activity in stem cell and neural development, and identify mechanisms by which this is disrupted in intellectual disability.
Original languageEnglish
Pages (from-to)1599-1611
Number of pages13
JournalCell Reports
Volume23
Issue number6
DOIs
Publication statusPublished - 8 May 2018

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Keywords

  • E3 ubiquitin ligase
  • RNF12/RLIM
  • X-linked intellectual disability
  • embryonic stem cells
  • intellectual disability
  • neural differentiation
  • proteasomal degradation
  • protein ubiquitylation
  • ubiquitin

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