The development of metastasis is a leading cause of cancer-related death that involves specific changes in the plasma membrane (PM) and nucleus of cancer cells. Elevated levels of membrane lipids, including sphingomyelin, cholesterol, and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), in the PM, contribute to changes in membrane rigidity, lipid raft formation, and actin polymerisation dynamics, processes that drive cell invasion. This review discusses the relationship between well-studied cytoplasmic phosphoinositides and their lesser-known nuclear counterparts, highlighting their functional role in metastatic progression. Nuclear phosphoinositides, particularly PI(4,5)P2, are essential for regulating transcription factors and chromatin organisation, thereby shaping gene expression patterns. We also explore the role of PI(4,5)P2 and its metabolism in cancer cell invasiveness and metastasis, proposing a model in which the dysregulation of cytosolic and/or nuclear PI(4,5)P2 pool triggers malignant transformation. Understanding the PI(4,5)P2-related mechanisms underlying metastasis may provide insights into potential therapeutic targets, paving the way for more effective therapies and improved patient outcomes.

• Klíčová slova
• Biocondensates, Cancer, HPV, Metastasis, Nucleus, Phosphatidylinositol 4,5-bisphosphate,
• MeSH
• buněčná membrána * metabolismus   MeSH
• buněčné jádro * metabolismus   MeSH
• fosfatidylinositol-4,5-difosfát * metabolismus   genetika   MeSH
• lidé MeSH
• membránové mikrodomény metabolismus   MeSH
• metastázy nádorů MeSH
• nádory * metabolismus   patologie   genetika   MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• fosfatidylinositol-4,5-difosfát * MeSH

The RNA content is crucial for the formation of nuclear compartments, such as nuclear speckles and nucleoli. Phosphatidylinositol 4,5-bisphosphate (PIP2) is found in nuclear speckles, nucleoli, and nuclear lipid islets and is involved in RNA polymerase I/II transcription. Intriguingly, the nuclear localization of PIP2 was also shown to be RNA-dependent. We therefore investigated whether PIP2 and RNA cooperate in the establishment of nuclear architecture. In this study, we unveiled the RNA-dependent PIP2-associated (RDPA) nuclear proteome in human cells by mass spectrometry. We found that intrinsically disordered regions (IDRs) with polybasic PIP2-binding K/R motifs are prevalent features of RDPA proteins. Moreover, these IDRs of RDPA proteins exhibit enrichment for phosphorylation, acetylation, and ubiquitination sites. Our results show for the first time that the RDPA protein Bromodomain-containing protein 4 (BRD4) associates with PIP2 in the RNA-dependent manner via electrostatic interactions, and that altered PIP2 levels affect the number of nuclear foci of BRD4 protein. Thus, we propose that PIP2 spatiotemporally orchestrates nuclear processes through association with RNA and RDPA proteins and affects their ability to form foci presumably via phase separation. This suggests the pivotal role of PIP2 in the establishment of a functional nuclear architecture competent for gene expression.

• MeSH
• buněčné jádro * metabolismus   genetika   MeSH
• fosfatidylinositol-4,5-difosfát * metabolismus   MeSH
• fosforylace MeSH
• jaderné proteiny * metabolismus   genetika   MeSH
• lidé MeSH
• proteiny buněčného cyklu metabolismus   genetika   MeSH
• proteiny obsahující bromodoménu MeSH
• RNA metabolismus   genetika   MeSH
• transkripční faktory * metabolismus   genetika   MeSH
• vazba proteinů MeSH
• vnitřně neuspořádané proteiny * metabolismus   genetika   chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• BRD4 protein, human MeSH Prohlížeč
• fosfatidylinositol-4,5-difosfát * MeSH
• jaderné proteiny * MeSH
• proteiny buněčného cyklu MeSH
• proteiny obsahující bromodoménu MeSH
• RNA MeSH
• transkripční faktory * MeSH
• vnitřně neuspořádané proteiny * MeSH

Lamins, the nuclear intermediate filaments, are important regulators of nuclear structural integrity as well as nuclear functional processes such as DNA transcription, replication and repair, and epigenetic regulations. A portion of phosphorylated lamin A/C localizes to the nuclear interior in interphase, forming a lamin A/C pool with specific properties and distinct functions. Nucleoplasmic lamin A/C molecular functions are mainly dependent on its binding partners; therefore, revealing new interactions could give us new clues on the lamin A/C mechanism of action. In the present study, we show that lamin A/C interacts with nuclear phosphoinositides (PIPs), and with nuclear myosin I (NM1). Both NM1 and nuclear PIPs have been previously reported as important regulators of gene expression and DNA damage/repair. Furthermore, phosphorylated lamin A/C forms a complex with NM1 in a phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2)-dependent manner in the nuclear interior. Taken together, our study reveals a previously unidentified interaction between phosphorylated lamin A/C, NM1, and PI(4,5)P2 and suggests new possible ways of nucleoplasmic lamin A/C regulation, function, and importance for the formation of functional nuclear microdomains.

• Klíčová slova
• NM1, PI(4,5)P2, cell nucleus, lamin A/C, nuclear lamina, nuclear myosin 1, nucleoplasm, phosphoinositides, phosphorylation,
• MeSH
• buněčné jádro * metabolismus   MeSH
• interfáze MeSH
• intermediární filamenta metabolismus   MeSH
• lamin typ A * metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• lamin typ A * MeSH

The many functions of phosphoinositides in cytosolic signaling were extensively studied; however, their activities in the cell nucleus are much less clear. In this review, we summarize data about their nuclear localization and metabolism, and review the available literature on their involvements in chromatin remodeling, gene transcription, and RNA processing. We discuss the molecular mechanisms via which nuclear phosphoinositides, in particular phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2), modulate nuclear processes. We focus on PI(4,5)P2's role in the modulation of RNA polymerase I activity, and functions of the nuclear lipid islets-recently described nucleoplasmic PI(4,5)P2-rich compartment involved in RNA polymerase II transcription. In conclusion, the high impact of the phosphoinositide-protein complexes on nuclear organization and genome functions is only now emerging and deserves further thorough studies.

• Klíčová slova
• cell nucleus, gene expression, genome, phosphoinositides,
• MeSH
• buněčné jádro genetika   metabolismus   MeSH
• Eukaryota genetika   metabolismus   MeSH
• fosfatidylinositol-4,5-difosfát metabolismus   MeSH
• genetická transkripce MeSH
• genom * MeSH
• posttranskripční úpravy RNA MeSH
• restrukturace chromatinu MeSH
• RNA-polymerasa I metabolismus   MeSH
• RNA-polymerasa II metabolismus   MeSH
• vazba proteinů fyziologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• fosfatidylinositol-4,5-difosfát MeSH
• RNA-polymerasa I MeSH
• RNA-polymerasa II MeSH

One of the most studied phosphoinositides is phosphatidylinositol 4,5-bisphosphate (PIP2), which localizes to the plasma membrane, nuclear speckles, small foci in the nucleoplasm, and to the nucleolus in mammalian cells. Here, we show that PIP2 also localizes to the nucleus in prophase I, during the gametogenesis of C. elegans hermaphrodite. The depletion of PIP2 by type I PIP kinase (PPK-1) kinase RNA interference results in an altered chromosome structure and leads to various defects during meiotic progression. We observed a decreased brood size and aneuploidy in progeny, defects in synapsis, and crossover formation. The altered chromosome structure is reflected in the increased transcription activity of a tightly regulated process in prophase I. To elucidate the involvement of PIP2 in the processes during the C. elegans development, we identified the PIP2-binding partners, leucine-rich repeat (LRR-1) protein and proteasome subunit beta 4 (PBS-4), pointing to its involvement in the ubiquitin⁻proteasome pathway.

• Klíčová slova
• C. elegans, PPK-1, nucleus, phosphatidylinositol 4,5-bisphosphate,
• MeSH
• buněčné jádro metabolismus   MeSH
• Caenorhabditis elegans genetika   růst a vývoj   metabolismus   MeSH
• chromozomy chemie   MeSH
• fosfatidylinositol-4,5-difosfát metabolismus   MeSH
• fosfotransferasy s alkoholovou skupinou jako akceptorem genetika   MeSH
• gametogeneze * MeSH
• hermafroditické organismy genetika   růst a vývoj   metabolismus   MeSH
• profáze meiózy I MeSH
• proteasomový endopeptidasový komplex metabolismus   MeSH
• proteiny Caenorhabditis elegans genetika   MeSH
• proteiny s repeticemi bohatými na leucin MeSH
• proteiny metabolismus   MeSH
• RNA interference MeSH
• vývojová regulace genové exprese MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fosfatidylinositol-4,5-difosfát MeSH
• fosfotransferasy s alkoholovou skupinou jako akceptorem MeSH
• Ppk-1 protein, C elegans MeSH Prohlížeč
• proteasomový endopeptidasový komplex MeSH
• proteiny Caenorhabditis elegans MeSH
• proteiny s repeticemi bohatými na leucin MeSH
• proteiny MeSH

Even though the majority of knowledge about phospholipids comes from their cytoplasmic functions, in the last decade, it has been shown that nuclear phospholipids and their building blocks, inositol phosphates, have many important roles in the cell nucleus. There are clear connections of phospholipids with the regulation of gene expression and chromatin biology, however, this review focuses on less known functions of nuclear phospholipids in connection with the epigenome regulation. In particular, we highlight the roles of nuclear phospholipids and inositol phosphates that involve histone modifications, such as acetylation or methylation, tightly connected with the cell physiology. This demonstrates the importance of nuclear phospholipids in the regulation of cellular processes, and should encourage further research of nuclear phospholipids and inositol phosphates.

• Klíčová slova
• Acetylation, Inositol phosphate, Methylation, Phosphoinositide, Phospholipids,
• MeSH
• chromatin chemie   metabolismus   MeSH
• epigeneze genetická * genetika   MeSH
• fosfolipidy chemie   metabolismus   MeSH
• inositolfosfáty chemie   metabolismus   MeSH
• lidé MeSH
• molekulární struktura MeSH
• regulace genové exprese MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• chromatin MeSH
• fosfolipidy MeSH
• inositolfosfáty MeSH

Phosphoinositides (PIs) are glycerol-based phospholipids containing hydrophilic inositol ring. The inositol ring is mono-, bis-, or tris-phosphorylated yielding seven PIs members. Ample evidence shows that PIs localize both to the cytoplasm and to the nucleus. However, tools for direct visualization of nuclear PIs are limited and many studies thus employ indirect approaches, such as staining of their metabolic enzymes. Since localization and mobility of PIs differ from their metabolic enzymes, these approaches may result in incomplete data. In this paper, we tested commercially available PIs antibodies by light microscopy on fixed cells, tested their specificity using protein-lipid overlay assay and blocking assay, and compared their staining patterns. Additionally, we prepared recombinant PIs-binding domains and tested them on both fixed and live cells by light microscopy. The results provide a useful overview of usability of the tools tested and stress that the selection of adequate tools is critical. Knowing the localization of individual PIs in various functional compartments should enable us to better understand the roles of PIs in the cell nucleus.

• Klíčová slova
• Nucleus, PI(4)P, PI(4,5)P2, Phosphoinositides,
• MeSH
• buněčné jadérko chemie   metabolismus   MeSH
• fluorescenční mikroskopie MeSH
• fluorescenční protilátková technika nepřímá MeSH
• fosfatidylinositoly analýza   imunologie   metabolismus   MeSH
• konfokální mikroskopie MeSH
• kultivované buňky MeSH
• lidé MeSH
• protilátky imunologie   MeSH
• reakce antigenu s protilátkou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fosfatidylinositoly MeSH
• protilátky MeSH