PIP4K2B is mechanoresponsive and controls heterochromatin-driven nuclear softening through UHRF1.
Humans
1-Phosphatidylinositol 4-Kinase
/ metabolism
CCAAT-Enhancer-Binding Proteins
/ genetics
Cell Nucleus
/ metabolism
Heterochromatin
/ genetics
Neoplasms
/ metabolism
Phosphatidylinositol Phosphates
/ metabolism
Protein Isoforms
/ metabolism
Signal Transduction
Ubiquitin-Protein Ligases
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
14 03 2023
14 03 2023
Historique:
received:
04
04
2022
accepted:
23
02
2023
entrez:
15
3
2023
pubmed:
16
3
2023
medline:
17
3
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36918565
doi: 10.1038/s41467-023-37064-0
pii: 10.1038/s41467-023-37064-0
pmc: PMC10015053
doi:
Substances chimiques
1-Phosphatidylinositol 4-Kinase
EC 2.7.1.67
CCAAT-Enhancer-Binding Proteins
0
Heterochromatin
0
Phosphatidylinositol Phosphates
0
Protein Isoforms
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
UHRF1 protein, human
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1432Informations de copyright
© 2023. The Author(s).
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