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USP13 controls the stability of Aurora B impacting progression through the cell cycle

Oncogene volume 39, pages 6009–6023 (2020)Cite this article

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Abstract

Aurora B kinase plays essential roles in mitosis. Its protein levels increase before the onset of mitosis and sharply decrease during mitosis exit. The latter decrease is due to a balance between the actions of the E3 ubiquitin ligase anaphase-promoting complex or cyclosome (activated by the Cdh1 adapter), and the deubiquitinating enzyme USP35. Aurora B also executes important functions in interphase. Abnormal modulation of Aurora B in interphase leads to cell cycle defects often linked to aberrant chromosomal condensation and segregation. Very little is however known about how Aurora B levels are regulated in interphase. Here we found that USP13-associates with and stabilizes Aurora B in cells, especially before their entry into mitosis. In order for USP13 to exert its stabilizing effect on Aurora B, their association is promoted by the Aurora B-mediated phosphorylation of USP13 at Serine 114. We also present evidence that USP13 instigates Aurora B deubiquitination and/or protect it from degradation in a non-catalytic manner. In addition, we report that genetic or chemical modulation of the cellular levels/activity of USP13 affects unperturbed cell-cycle progression. Overall our study unveils the molecular and cellular connections of the USP13-Aurora B axis, which potentially participates in the rewiring of the cell cycle happening in cancer cells.

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Fig. 1: Aurora B phosphorylates USP13 at Serine 114.
Fig. 2: USP13 and Aurora B interact in vitro and in cells.
Fig. 3: Overexpression of USP13 stabilizes Aurora B protein levels.
Fig. 4: Downregulation of USP13 decreases Aurora B protein levels.
Fig. 5: USP13 regulates the cellular half-life of Aurora B.
Fig. 6: USP13 controls Aurora B stability via enzymatically-independent mechanisms.
Fig. 7: Overexpression of USP13 causes a prophase-like arrest.
Fig. 8: Downregulation of USP13 induces G1 arrest.

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Acknowledgements

Research in GJG’s laboratory was funded by grants from FWO (G0C7514N), BELSPO Interuniversity Attraction Poles (IAP-P7 – 07), VUB (starting ZAP credit & Interdisciplinary Research Program for Excellence on Cancer Research), and Innoviris (BB2B program). The collaboration between the laboratories of GJG and CL included a short-term scientific mission (ME) supported by the COST-EU program (Proteostasis). We are indebted to Yvon Elkrim for technical assistance with the flow cytometry analyses, and to Professors Luc Leyns and Peter Tompa (VUB- and VIB- Brussels, Belgium, respectively) for allowing access to some of their laboratories’ equipment.

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Author notes

  1. M. Angeles Ceregido

    Present address: GlaxoSmithKline, Avenue Pascal, 2-4-6, 1300, Wavre, Belgium

  2. Rogier Schepers

    Present address: VIB-KU Leuven Center for Cancer Biology, Campus Gasthuisberg, Herestraat, 49-B912, Leuven, Belgium

  3. Luis C. Ramos Paez

    Present address: Ablynx NV, Technologiepark 21, Zwijnaarde, 9052, Ghent, Belgium

  4. Esther La Monaca

    Present address: Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340, Beerse, Belgium

  5. Gustavo J. Gutierrez

    Present address: Galapagos NV, Generaal De Wittelaan L11 A3, 2800, Mechelen, Belgium

Authors and Affiliations

  1. Laboratory of Pathophysiological Cell Signaling, Department of Biology, Faculty of Science and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussels, Belgium

    Mara Esposito, Philippe Giron, M. Angeles Ceregido, Rogier Schepers, Luis C. Ramos Paez, Esther La Monaca & Gustavo J. Gutierrez

  2. Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK

    H. Begum Akman & Catherine Lindon

  3. Laboratory of Molecular and Medical Oncology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium

    Philippe Giron & Jacques De Greve

  4. CNRS-CRBM, 1919 Route de Mende, 34293, Montpellier, France

    Olivier Coux

  5. Laboratory of Cellular and Molecular Immunology, Department of Bioengineering, Faculty of Science and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussels, Belgium

    Carl De Trez

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Esposito, M., Akman, H.B., Giron, P. et al. USP13 controls the stability of Aurora B impacting progression through the cell cycle. Oncogene 39, 6009–6023 (2020). https://doi.org/10.1038/s41388-020-01396-8

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