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Sub-cellular Biochemistry 2022The distinct movements of macropinosome formation and maturation have corresponding biochemical activities which occur in a defined sequence of stages and transitions...
The distinct movements of macropinosome formation and maturation have corresponding biochemical activities which occur in a defined sequence of stages and transitions between those stages. Each stage in the process is regulated by variously phosphorylated derivatives of phosphatidylinositol (PtdIns) which reside in the cytoplasmic face of the membrane lipid bilayer. PtdIns derivatives phosphorylated at the 3' position of the inositol moiety, called 3' phosphoinositides (3'PIs), regulate different stages of the sequence. 3'PIs are synthesized by numerous phosphoinositide 3'-kinases (PI3K) and other lipid kinases and phosphatases, which are themselves regulated by small GTPases of the Ras superfamily. The combined actions of these enzymes localize four principal species of 3'PI to distinct domains of the plasma membrane or to discrete organelles, with distinct biochemical activities confined to those domains. Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P) and phosphatidylinositol (3,4)-bisphosphate (PtdIns(3,4)P) regulate the early stages of macropinosome formation, which include cell surface ruffling and constrictions of circular ruffles which close into macropinosomes. Phosphatidylinositol 3-phosphate (PtdIns3P) regulates macropinosome fusion with other macropinosomes and early endocytic organelles. Phosphatidylinositol (3,5)-bisphosphate (PtdIns(3,5)P) mediates macropinosome maturation and shrinkage, through loss of ions and water, and subsequent traffic to lysosomes. The different characteristic rates of macropinocytosis in different cell types indicate levels of regulation which may be governed by the cell's capacity to generate 3'PIs.
Topics: Cell Membrane; Endosomes; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Pinocytosis
PubMed: 35378706
DOI: 10.1007/978-3-030-94004-1_7 -
Nature Chemical Biology Apr 2023
Topics: Inositol; Phosphatidylinositols
PubMed: 36991166
DOI: 10.1038/s41589-023-01311-8 -
Advances in Experimental Medicine and... 2019The phox-homology (PX) domain is a phosphoinositide-binding domain conserved in all eukaryotes and present in 49 human proteins. Proteins containing PX domains, many of... (Review)
Review
The phox-homology (PX) domain is a phosphoinositide-binding domain conserved in all eukaryotes and present in 49 human proteins. Proteins containing PX domains, many of which are also known as sorting nexins (SNXs), have a large variety of functions in membrane trafficking, cell signaling, and lipid metabolism in association with membranes of the secretory and endocytic system. In this review we discuss the structural basis for both canonical lipid interactions with the endosome-enriched lipid phosphatidylinositol-3-phosphate (PtdIns3P) as well as non-canonical lipids that promote membrane association. We also describe recent advances in defining the diverse mechanisms by which PX domains interact with other proteins including the retromer trafficking complex and proteins secreted by bacterial pathogens. Like other membrane interacting domains, the attachment of PX domain proteins to specific membranes is often facilitated by additional interactions that contribute to binding avidity, and we discuss this coincidence detection for several known examples.
Topics: Animals; Biological Transport; Endosomes; Humans; Phosphatidylinositols; Protein Domains; Sorting Nexins
PubMed: 29569114
DOI: 10.1007/5584_2018_185 -
Seminars in Cell & Developmental Biology Nov 2016Phosphatidylinositol phosphates (PIPs) are membrane lipids with crucial roles during cell morphogenesis, including the establishment of cytoskeletal organization,... (Review)
Review
Phosphatidylinositol phosphates (PIPs) are membrane lipids with crucial roles during cell morphogenesis, including the establishment of cytoskeletal organization, membrane trafficking, cell polarity, cell-cycle control and signaling. Recent studies in mice (Mus musculus), fruit flies (Drosophila melanogaster) and other organisms have defined germ cell intrinsic requirements for these lipids and their regulatory enzymes in multiple aspects of sperm development. In particular, PIP levels are crucial in germline stem cell maintenance, spermatogonial proliferation and survival, spermatocyte cytokinesis, spermatid polarization, sperm tail formation, nuclear shaping, and production of mature, motile sperm. Here, we briefly review the stages of spermatogenesis and discuss the roles of PIPs and their regulatory enzymes in male germ cell development.
Topics: Animals; Humans; Male; Meiosis; Mitosis; Models, Biological; Phosphatidylinositols; Signal Transduction; Spermatogenesis; Spermatozoa
PubMed: 27321976
DOI: 10.1016/j.semcdb.2016.06.010 -
Current Topics in Microbiology and... 2022Improving the anti-tumour T cell response as a consequence of immunotherapy can result in eradication of tumour burden, however, the majority of patients fail with... (Review)
Review
Improving the anti-tumour T cell response as a consequence of immunotherapy can result in eradication of tumour burden, however, the majority of patients fail with current treatment regimens and so novel immunotherapies with greater efficacy and improved tolerability are needed. The phosphoinositide-3-kinase (PI3K) family members that are directly involved in cell signalling comprise PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ, with the latter two isoforms expressed primarily by leukocytes. The survival and optimal function of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSCs) is dependent on PI3Kδ, whereas tumour-associated macrophages (TAMs), use PI3Kγ. Blocking these signalling isoforms can boost development of effective anti-cancer immune responses and result in control of tumour burden. The dependence on different PI3K isoforms in immune cells makes targeting this pathway an attractive approach for tumour immunotherapy. Herein, we discuss how inhibiting specific PI3K isoforms in pro-tumoural Tregs, MDSCS and TAMs can unleash a powerful anti-tumour immune response, driven by CD8 T cells, capable of controlling tumour burden and consider how the immune response to therapy needs careful investigation, to identify both the correlates of successful treatment and those that impede the generation of robust anti-tumour responses. Furthermore, we review how combination immunotherapy approaches with both PI3K inhibitors and subsequent immune checkpoint blockade can potentiate the efficacy of monotherapy. Finally, we discuss the recent advances in the use of PI3K isoform-specific inhibitors as an immunotherapy for solid tumours in clinical trials.
Topics: CD8-Positive T-Lymphocytes; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Neoplasms; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phosphatidylinositols; Phosphoinositide-3 Kinase Inhibitors; Protein Isoforms
PubMed: 36243853
DOI: 10.1007/978-3-031-06566-8_16 -
Frontiers in Cellular and Infection... 2019Phosphatidylinositol (PtdIns) metabolism is indispensable in eukaryotes. Phosphoinositides (PIs) are phosphorylated derivatives of PtdIns and consist of seven species... (Review)
Review
Phosphatidylinositol (PtdIns) metabolism is indispensable in eukaryotes. Phosphoinositides (PIs) are phosphorylated derivatives of PtdIns and consist of seven species generated by reversible phosphorylation of the inositol moieties at the positions 3, 4, and 5. Each of the seven PIs has a unique subcellular and membrane domain distribution. In the enteric protozoan parasite , it has been previously shown that the PIs phosphatidylinositol 3-phosphate (PtdIns3P), PtdIns(4,5)P, and PtdIns(3,4,5)P are localized to phagosomes/phagocytic cups, plasma membrane, and phagocytic cups, respectively. The localization of these PIs in is similar to that in mammalian cells, suggesting that PIs have orthologous functions in . In contrast, the conservation of the enzymes that metabolize PIs in this organism has not been well-documented. In this review, we summarized the full repertoire of the PI kinases and PI phosphatases found in via a genome-wide survey of the current genomic information. appears to have 10 PI kinases and 23 PI phosphatases. It has a panel of evolutionarily conserved enzymes that generate all the seven PI species. However, class II PI 3-kinases, type II PI 4-kinases, type III PI 5-phosphatases, and PI 4P-specific phosphatases are not present. Additionally, regulatory subunits of class I PI 3-kinases and type III PI 4-kinases have not been identified. Instead, homologs of class I PI 3-kinases and PTEN, a PI 3-phosphatase, exist as multiple isoforms, which likely reflects that elaborate signaling cascades mediated by PtdIns(3,4,5)P are present in this organism. There are several enzymes that have the nuclear localization signal: one phosphatidylinositol phosphate (PIP) kinase, two PI 3-phosphatases, and one PI 5-phosphatase; this suggests that PI metabolism also has conserved roles related to nuclear functions in , as it does in model organisms.
Topics: 1-Phosphatidylinositol 4-Kinase; Animals; Cell Membrane; Cell Nucleus; Entamoeba histolytica; Phagosomes; Phosphatidylinositol 3-Kinases; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphotransferases (Alcohol Group Acceptor); Protein Isoforms; Signal Transduction
PubMed: 31245297
DOI: 10.3389/fcimb.2019.00150 -
Biomolecules Jun 2023Polyphosphoinositides (PPIns) are signalling messengers representing less than five per cent of the total phospholipid concentration within the cell. Despite their low... (Review)
Review
Polyphosphoinositides (PPIns) are signalling messengers representing less than five per cent of the total phospholipid concentration within the cell. Despite their low concentration, these lipids are critical regulators of various cellular processes, including cell cycle, differentiation, gene transcription, apoptosis and motility. PPIns are generated by the phosphorylation of the inositol head group of phosphatidylinositol (PtdIns). Different pools of PPIns are found at distinct subcellular compartments, which are regulated by an array of kinases, phosphatases and phospholipases. Six of the seven PPIns species have been found in the nucleus, including the nuclear envelope, the nucleoplasm and the nucleolus. The identification and characterisation of PPIns interactor and effector proteins in the nucleus have led to increasing interest in the role of PPIns in nuclear signalling. However, the regulation and functions of PPIns in the nucleus are complex and are still being elucidated. This review summarises our current understanding of the localisation, biogenesis and physiological functions of the different PPIns species in the nucleus.
Topics: Phosphatidylinositols; Cell Nucleus; Phosphatidylinositol Phosphates; Cell Nucleolus; Nuclear Envelope
PubMed: 37509085
DOI: 10.3390/biom13071049 -
International Journal For Parasitology Jun 2018Phosphoinositides are the phosphorylated derivatives of the structural membrane phospholipid phosphatidylinositol. Single or combined phosphorylation at the 3, 4 and 5... (Review)
Review
Phosphoinositides are the phosphorylated derivatives of the structural membrane phospholipid phosphatidylinositol. Single or combined phosphorylation at the 3, 4 and 5 positions of the inositol ring gives rise to the seven different species of phosphoinositides. All are quantitatively minor components of cellular membranes but have been shown to have important functions in multiple cellular processes. Here we describe our current knowledge of phosphoinositide metabolism and functions in apicomplexan parasites, mainly focusing on Toxoplasma gondii and Plasmodium spp. Even though our understanding is still rudimentary, phosphoinositides have already shown their importance in parasite biology and revealed some very particular and parasite-specific functions. Not surprisingly, there is a strong potential for phosphoinositide synthesis to be exploited for future anti-parasitic drug development.
Topics: Animals; Apicomplexa; Lipid Metabolism; Parasites; Phosphatidylinositols
PubMed: 29596862
DOI: 10.1016/j.ijpara.2018.01.009 -
Biochemical Society Transactions Apr 2016Cellular membranes communicate extensively via contact sites that form between two membranes. Such sites allow exchange of specific ions, lipids or proteins between two... (Review)
Review
Cellular membranes communicate extensively via contact sites that form between two membranes. Such sites allow exchange of specific ions, lipids or proteins between two compartments without content mixing, thereby preserving organellar architecture during the transfer process. Even though the molecular compositions of membrane contact sites are diverse, it is striking that several of these sites, including contact sites between the endoplasmic reticulum (ER) and endosomes, Golgi and the plasma membrane (PM), and contact sites between lysosomes and peroxisomes, contain phosphorylated derivatives of phosphatidylinositol known as phosphoinositides. In this mini-review we discuss the involvement and functions of phosphoinositides in membrane contact sites.
Topics: Animals; Binding Sites; Cell Membrane; Humans; Intracellular Membranes; Organelles; Phosphatidylinositols
PubMed: 27068950
DOI: 10.1042/BST20150190 -
Biochimica Et Biophysica Acta.... Sep 2021Phosphatidylinositol is the parent lipid for the synthesis of seven phosphorylated inositol lipids and each of them play specific roles in numerous processes including... (Review)
Review
Phosphatidylinositol is the parent lipid for the synthesis of seven phosphorylated inositol lipids and each of them play specific roles in numerous processes including receptor-mediated signalling, actin cytoskeleton dynamics and membrane trafficking. PI synthesis is localised to the endoplasmic reticulum (ER) whilst its phosphorylated derivatives are found in other organelles where the lipid kinases also reside. Phosphorylation of PI to phosphatidylinositol (4,5) bisphosphate (PI(4,5)P) at the plasma membrane and to phosphatidylinositol 4-phosphate (PI4P) at the Golgi are key events in lipid signalling and Golgi function respectively. Here we review a family of proteins, phosphatidylinositol transfer proteins (PITPs), that can mobilise PI from the ER to provide the substrate to the resident kinases for phosphorylation. Recent studies identify specific and overlapping functions for the three soluble PITPs (PITPα, PITPβ and PITPNC1) in phospholipase C signalling, neuronal function, membrane trafficking, viral replication and in cancer metastases.
Topics: Biological Transport; Cell Membrane; Endoplasmic Reticulum; Phosphatidylinositols; Signal Transduction
PubMed: 34111527
DOI: 10.1016/j.bbalip.2021.158985