PIP4K2B is a mechanosensor and induces heterochromatin-driven nuclear softening through UHRF1

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 localization. Here, we unveil the role for PIP4K2B as mechanosensor. PIP4K2B protein level, indeed, strongly decreases in cells growing on soft substrates. Its direct silencing or pharmacological inhibition, mimicking cell response to soft, 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.

Flow-induced mechanical coupling between perinuclear actin cap and nucleus governs spatiotemporal regulation of YAP transport

“…To verify the reliability of Brillouin microscopy, we quantified the degree of chromatin compaction and found a strong correlation with the nuclear stiffness, which is consistent with the published well-proven conventional mechanical measurements 28,48,49 . In addition, it has been reported that the degree of chromatin compaction is associated with the localization of YAP 50,51 . For example, epithelial cells exposed on convex curvature show an elevated nuclear presence of YAP and less condensed chromatin, while the nucleus on concave curvatures contains more condensed chromatin with cytoplasmic YAP 52 .…”

Chromatin condensates tune nuclear mechano-sensing in Kabuki Syndrome by constraining cGAS activation

“…5i, j), indicating that the altered nuclear shape was not solely dependent on the relative abundance of A/C. To measure the NE tensional state of MSCs directly in response to ECM stiffness, we adopted the Mini Nesprin 1 reporter as the FRET sensor 47 . We found that while in the MLL4 WT MSCs the NE tension increased with the stiffening of the matrix, this responsiveness was impaired upon MLL4 LoF (Fig 5f).…”

Hippo and PI5P4K signaling intersect to control the transcriptional activation of YAP

“…Because PI5P4Ks control intracellular pools of PI5P, we hypothesized that the increased MOB-LATS binding in the absence of the most active isoforms of PI5P4Ks may be mediated by PI5P, the substrate of these kinases. Phospholipids regulate components of the Hippo pathway (8)(9)(10)(11)(12), although LATS does not appear to bind to PI5P or PI4,5P 2 (9). Therefore, we focused our attention on MOB1.…”

“…Several phospholipids regulate the Hippo pathway (8)(9)(10)(11)(12), which consists of four major kinases, mammalian Ste20-like kinases 1 and 2 (MST1/2) and large tumor suppressor LATS1 and LAT2 (LATS1/2), as well as the associated adaptor proteins SAV and MOB1. The main downstream target of Hippo pathway, Yes-associated protein (YAP), activates various transcriptional programs related to cell growth.…”