Increased p53 signaling impairs neural differentiation in HUWE1-promoted intellectual disabilities

Rossana Aprigliano; Merdane Ezgi Aksu; Stefano Bradamante; Boris Mihaljevic; Wei Wang; Kristin Rian; Nicola P. Montaldo; Kayla Mae Grooms; Sarah L. Fordyce Martin; Diana L. Bordin; Matthias Bosshard; Yunhui Peng; Emil Alexov; Cindy Skinner; Nina-Beate Liabakk; Gareth J. Sullivan; Magnar Bjørås; Charles E. Schwartz; Barbara van Loon

Cell Reports Medicine (Apr 2021)

Increased p53 signaling impairs neural differentiation in HUWE1-promoted intellectual disabilities

Rossana Aprigliano,
Merdane Ezgi Aksu,
Stefano Bradamante,
Boris Mihaljevic,
Wei Wang,
Kristin Rian,
Nicola P. Montaldo,
Kayla Mae Grooms,
Sarah L. Fordyce Martin,
Diana L. Bordin,
Matthias Bosshard,
Yunhui Peng,
Emil Alexov,
Cindy Skinner,
Nina-Beate Liabakk,
Gareth J. Sullivan,
Magnar Bjørås,
Charles E. Schwartz,
Barbara van Loon

Affiliations

Rossana Aprigliano: Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7049 Trondheim, Norway; Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zürich, Switzerland
Merdane Ezgi Aksu: Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7049 Trondheim, Norway
Stefano Bradamante: Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7049 Trondheim, Norway; Department of Pathology and Medical Genetics, St. Olavs University Hospital, 7049 Trondheim, Norway
Boris Mihaljevic: Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7049 Trondheim, Norway
Wei Wang: Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7049 Trondheim, Norway
Kristin Rian: Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7049 Trondheim, Norway
Nicola P. Montaldo: Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7049 Trondheim, Norway
Kayla Mae Grooms: Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7049 Trondheim, Norway
Sarah L. Fordyce Martin: Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7049 Trondheim, Norway
Diana L. Bordin: Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7049 Trondheim, Norway
Matthias Bosshard: Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zürich, Switzerland
Yunhui Peng: Computational Biophysics and Bioinformatics, Department of Physics and Astronomy, Clemson University, Clemson, SC 29631, USA
Emil Alexov: Computational Biophysics and Bioinformatics, Department of Physics and Astronomy, Clemson University, Clemson, SC 29631, USA
Cindy Skinner: Greenwood Genetic Center, Greenwood, SC 29646, USA
Nina-Beate Liabakk: Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7049 Trondheim, Norway
Gareth J. Sullivan: Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0315 Oslo, Norway; Hybrid Technology Hub, Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, 0315 Oslo, Norway
Magnar Bjørås: Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7049 Trondheim, Norway; Department of Pathology and Medical Genetics, St. Olavs University Hospital, 7049 Trondheim, Norway; Department of Microbiology, Oslo University Hospital, Department of Medical Biochemistry, Oslo University Hospital and University of Oslo, 0372 Oslo, Norway
Charles E. Schwartz: Greenwood Genetic Center, Greenwood, SC 29646, USA
Barbara van Loon: Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7049 Trondheim, Norway; Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zürich, Switzerland; Department of Pathology and Medical Genetics, St. Olavs University Hospital, 7049 Trondheim, Norway; Corresponding author

Journal volume & issue: Vol. 2, no. 4
p. 100240

Abstract

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Summary: Essential E3 ubiquitin ligase HUWE1 (HECT, UBA, and WWE domain containing 1) regulates key factors, such as p53. Although mutations in HUWE1 cause heterogenous neurodevelopmental X-linked intellectual disabilities (XLIDs), the disease mechanisms common to these syndromes remain unknown. In this work, we identify p53 signaling as the central process altered in HUWE1-promoted XLID syndromes. By focusing on Juberg-Marsidi syndrome (JMS), one of the severest XLIDs, we show that increased p53 signaling results from p53 accumulation caused by HUWE1 p.G4310R destabilization. This further alters cell-cycle progression and proliferation in JMS cells. Modeling of JMS neurodevelopment reveals majorly impaired neural differentiation accompanied by increased p53 signaling. The neural differentiation defects can be successfully rescued by reducing p53 levels and restoring the expression of p53 target genes, in particular CDKN1A/p21. In summary, our findings suggest that increased p53 signaling underlies HUWE1-promoted syndromes and impairs XLID JMS neural differentiation.

Published in Cell Reports Medicine

ISSN: 2666-3791 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Medicine (General)
Website: https://www.cell.com/cell-reports-medicine

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