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PIP4K2B is mechanoresponsive and controls heterochromatin-driven nuclear softening through UHRF1

Author

Listed:
  • Alessandro Poli

    (IFOM ETS - The AIRC Institute of Molecular Oncology)

  • Fabrizio A. Pennacchio

    (IFOM ETS - The AIRC Institute of Molecular Oncology)

  • Andrea Ghisleni

    (IFOM ETS - The AIRC Institute of Molecular Oncology)

  • Mariagrazia Gennaro

    (IFOM ETS - The AIRC Institute of Molecular Oncology)

  • Margaux Lecacheur

    (IFOM ETS - The AIRC Institute of Molecular Oncology)

  • Paulina Nastały

    (University of Gdańsk and Medical University of Gdańsk)

  • Michele Crestani

    (IFOM ETS - The AIRC Institute of Molecular Oncology)

  • Francesca M. Pramotton

    (EMPA-Materials Science and Technology
    Institute for Mechanical Systems, ETH)

  • Fabio Iannelli

    (IFOM ETS - The AIRC Institute of Molecular Oncology)

  • Galina Beznusenko

    (IFOM ETS - The AIRC Institute of Molecular Oncology)

  • Alexander A. Mironov

    (IFOM ETS - The AIRC Institute of Molecular Oncology)

  • Valeria Panzetta

    (University of Naples Federico II
    University of Naples Federico II
    Istituto Italiano di Tecnologia, IIT@CRIB)

  • Sabato Fusco

    (University of Molise)

  • Bhavwanti Sheth

    (University of Southampton)

  • Dimos Poulikakos

    (Institute for Mechanical Systems, ETH)

  • Aldo Ferrari

    (Institute for Mechanical Systems, ETH)

  • Nils Gauthier

    (IFOM ETS - The AIRC Institute of Molecular Oncology)

  • Paolo A. Netti

    (University of Naples Federico II
    University of Naples Federico II
    Istituto Italiano di Tecnologia, IIT@CRIB)

  • Nullin Divecha

    (University of Southampton)

  • Paolo Maiuri

    (IFOM ETS - The AIRC Institute of Molecular Oncology
    University of Naples Federico II)

Abstract

Phosphatidylinositol-5-phosphate (PtdIns5P)−4-kinases (PIP4Ks) are stress-regulated phosphoinositide kinases able to phosphorylate PtdIns5P to PtdIns(4,5)P2. In cancer patients their expression is typically associated with bad prognosis. Among the three PIP4K isoforms expressed in mammalian cells, PIP4K2B is the one with more prominent nuclear localisation. Here, we unveil the role of PIP4K2B as a mechanoresponsive enzyme. PIP4K2B protein level strongly decreases in cells growing on soft substrates. Its direct silencing or pharmacological inhibition, mimicking cell response to softness, triggers a concomitant reduction of the epigenetic regulator UHRF1 and induces changes in nuclear polarity, nuclear envelope tension and chromatin compaction. This substantial rewiring of the nucleus mechanical state drives YAP cytoplasmic retention and impairment of its activity as transcriptional regulator, finally leading to defects in cell spreading and motility. Since YAP signalling is essential for initiation and growth of human malignancies, our data suggest that potential therapeutic approaches targeting PIP4K2B could be beneficial in the control of the altered mechanical properties of cancer cells.

Suggested Citation

  • Alessandro Poli & Fabrizio A. Pennacchio & Andrea Ghisleni & Mariagrazia Gennaro & Margaux Lecacheur & Paulina Nastały & Michele Crestani & Francesca M. Pramotton & Fabio Iannelli & Galina Beznusenko , 2023. "PIP4K2B is mechanoresponsive and controls heterochromatin-driven nuclear softening through UHRF1," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37064-0
    DOI: 10.1038/s41467-023-37064-0
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    References listed on IDEAS

    as
    1. Dean J. Procter & Colleen Furey & Arturo G. Garza-Gongora & Steven T. Kosak & Derek Walsh, 2020. "Cytoplasmic control of intranuclear polarity by human cytomegalovirus," Nature, Nature, vol. 587(7832), pages 109-114, November.
    2. Mayumi Kitagawa & Pei-Ju Liao & Kyung Hee Lee & Jasmine Wong & See Cheng Shang & Noriaki Minami & Oltea Sampetrean & Hideyuki Saya & Dai Lingyun & Nayana Prabhu & Go Ka Diam & Radoslaw Sobota & Andrea, 2017. "Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    3. Giorgia Nardone & Jorge Oliver-De La Cruz & Jan Vrbsky & Cecilia Martini & Jan Pribyl & Petr Skládal & Martin Pešl & Guido Caluori & Stefania Pagliari & Fabiana Martino & Zuzana Maceckova & Marian Haj, 2017. "YAP regulates cell mechanics by controlling focal adhesion assembly," Nature Communications, Nature, vol. 8(1), pages 1-13, August.
    4. Lucia E. Rameh & Kimberley F. Tolias & Brian C. Duckworth & Lewis C. Cantley, 1997. "A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate," Nature, Nature, vol. 390(6656), pages 192-196, November.
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    Cited by:

    1. Andrea Ghisleni & Mayte Bonilla-Quintana & Michele Crestani & Zeno Lavagnino & Camilla Galli & Padmini Rangamani & Nils C. Gauthier, 2024. "Mechanically induced topological transition of spectrin regulates its distribution in the mammalian cell cortex," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    2. Fabrizio A. Pennacchio & Alessandro Poli & Francesca Michela Pramotton & Stefania Lavore & Ilaria Rancati & Mario Cinquanta & Daan Vorselen & Elisabetta Prina & Orso Maria Romano & Aldo Ferrari & Matt, 2024. "N2FXm, a method for joint nuclear and cytoplasmic volume measurements, unravels the osmo-mechanical regulation of nuclear volume in mammalian cells," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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