RNF12 X-Linked Intellectual Disability Mutations Disrupt E3 Ligase Activity and Neural Differentiation
Summary: 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 explor...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-05-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718305515 |
| _version_ | 1811324019875512320 |
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| author | Francisco Bustos Anna Segarra-Fas Viduth K. Chaugule Lennart Brandenburg Emma Branigan Rachel Toth Thomas Macartney Axel Knebel Ronald T. Hay Helen Walden Greg M. Findlay |
| author_facet | Francisco Bustos Anna Segarra-Fas Viduth K. Chaugule Lennart Brandenburg Emma Branigan Rachel Toth Thomas Macartney Axel Knebel Ronald T. Hay Helen Walden Greg M. Findlay |
| author_sort | Francisco Bustos |
| collection | DOAJ |
| description | Summary: 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 developmentally relevant substrates. XLID mutants disrupt distinct RNF12 functional modules by either 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. : Bustos et al. show that the RNF12 E3 ubiquitin ligase regulates stem cell maintenance and neuronal differentiation. They demonstrate that RNF12/RLIM mutations identified in X-linked intellectual disability patients disrupt regions required for catalytic activity, which leads to compromised stem cell maintenance and abnormal neural differentiation. Keywords: ubiquitin, protein ubiquitylation, E3 ubiquitin ligase, proteasomal degradation, RNF12/RLIM, intellectual disability, X-linked intellectual disability, embryonic stem cells, neural differentiation |
| first_indexed | 2024-04-13T14:06:52Z |
| format | Article |
| id | doaj.art-a7ffd6fa9df048268b625e400ceb92e8 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-13T14:06:52Z |
| publishDate | 2018-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-a7ffd6fa9df048268b625e400ceb92e82022-12-22T02:43:54ZengElsevierCell Reports2211-12472018-05-0123615991611RNF12 X-Linked Intellectual Disability Mutations Disrupt E3 Ligase Activity and Neural DifferentiationFrancisco Bustos0Anna Segarra-Fas1Viduth K. Chaugule2Lennart Brandenburg3Emma Branigan4Rachel Toth5Thomas Macartney6Axel Knebel7Ronald T. Hay8Helen Walden9Greg M. Findlay10The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, The University of Dundee, Dundee DD1 5EH, UKThe MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, The University of Dundee, Dundee DD1 5EH, UKInstitute of Molecular Cell and Systems Biology, The University of Glasgow, Glasgow G12 8QQ, UKThe MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, The University of Dundee, Dundee DD1 5EH, UKCentre for Gene Regulation and Expression, School of Life Sciences, The University of Dundee, Dundee DD1 5EH, UKThe MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, The University of Dundee, Dundee DD1 5EH, UKThe MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, The University of Dundee, Dundee DD1 5EH, UKThe MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, The University of Dundee, Dundee DD1 5EH, UKCentre for Gene Regulation and Expression, School of Life Sciences, The University of Dundee, Dundee DD1 5EH, UKInstitute of Molecular Cell and Systems Biology, The University of Glasgow, Glasgow G12 8QQ, UKThe MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, The University of Dundee, Dundee DD1 5EH, UK; Corresponding authorSummary: 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 developmentally relevant substrates. XLID mutants disrupt distinct RNF12 functional modules by either 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. : Bustos et al. show that the RNF12 E3 ubiquitin ligase regulates stem cell maintenance and neuronal differentiation. They demonstrate that RNF12/RLIM mutations identified in X-linked intellectual disability patients disrupt regions required for catalytic activity, which leads to compromised stem cell maintenance and abnormal neural differentiation. Keywords: ubiquitin, protein ubiquitylation, E3 ubiquitin ligase, proteasomal degradation, RNF12/RLIM, intellectual disability, X-linked intellectual disability, embryonic stem cells, neural differentiationhttp://www.sciencedirect.com/science/article/pii/S2211124718305515 |
| spellingShingle | Francisco Bustos Anna Segarra-Fas Viduth K. Chaugule Lennart Brandenburg Emma Branigan Rachel Toth Thomas Macartney Axel Knebel Ronald T. Hay Helen Walden Greg M. Findlay RNF12 X-Linked Intellectual Disability Mutations Disrupt E3 Ligase Activity and Neural Differentiation Cell Reports |
| title | RNF12 X-Linked Intellectual Disability Mutations Disrupt E3 Ligase Activity and Neural Differentiation |
| title_full | RNF12 X-Linked Intellectual Disability Mutations Disrupt E3 Ligase Activity and Neural Differentiation |
| title_fullStr | RNF12 X-Linked Intellectual Disability Mutations Disrupt E3 Ligase Activity and Neural Differentiation |
| title_full_unstemmed | RNF12 X-Linked Intellectual Disability Mutations Disrupt E3 Ligase Activity and Neural Differentiation |
| title_short | RNF12 X-Linked Intellectual Disability Mutations Disrupt E3 Ligase Activity and Neural Differentiation |
| title_sort | rnf12 x linked intellectual disability mutations disrupt e3 ligase activity and neural differentiation |
| url | http://www.sciencedirect.com/science/article/pii/S2211124718305515 |
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