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Plant Science : An International... Apr 2019Plant cells use autophagy to degrade their own cytoplasm in vacuoles, thereby not only recycling their breakdown products, but also ensuring the homeostasis of essential... (Review)
Review
Plant cells use autophagy to degrade their own cytoplasm in vacuoles, thereby not only recycling their breakdown products, but also ensuring the homeostasis of essential cytoplasmic constituents and organelles. Plants and other eukaryotes have a conserved set of core Autophagy-related (ATG) genes involved in the biogenesis of the autophagosome, the main autophagic compartment destined for the lytic vacuole. In the past decade, the core ATG genes were isolated from several plant species. The core ATG proteins include the components of the VACUOLAR PROTEIN SORTING 34 (VPS34) complex that is responsible for the local production of phosphatidylinositol 3-phosphate (PI3P) at the site of autophagosome formation. Dissecting the roles of PI3P and its effectors in autophagy is challenging, because of the multi-faceted links between autophagosomal and endosomal systems. This review highlights recent studies on putative plant PI3P effectors involved in autophagosome dynamics. Molecular mechanisms underlying the requirement of PI3P for autophagosome biogenesis and trafficking are also discussed.
Topics: Arabidopsis Proteins; Autophagy; Endosomes; Phosphatidylinositol Phosphates; Phosphatidylinositols; Plant Cells; Vesicular Transport Proteins
PubMed: 30824047
DOI: 10.1016/j.plantsci.2019.01.017 -
Autophagy Sep 2023Although PIKFYVE phosphoinositide kinase inhibitors can selectively eliminate PIKFYVE-dependent human cancer cells and , the basis for this selectivity has remained...
Although PIKFYVE phosphoinositide kinase inhibitors can selectively eliminate PIKFYVE-dependent human cancer cells and , the basis for this selectivity has remained elusive. Here we show that the sensitivity of cells to the PIKFYVE inhibitor WX8 is not linked to PIKFYVE expression, macroautophagic/autophagic flux, the BRAF mutation, or ambiguous inhibitor specificity. PIKFYVE dependence results from a deficiency in the PIP5K1C phosphoinositide kinase, an enzyme required for conversion of phosphatidylinositol-4-phosphate (PtdIns4P) into phosphatidylinositol-4,5-bisphosphate (PtdIns[4,5]P/PIP2), a phosphoinositide associated with lysosome homeostasis, endosome trafficking, and autophagy. PtdIns(4,5)P is produced via two independent pathways. One requires PIP5K1C; the other requires PIKFYVE and PIP4K2C to convert PtdIns3P into PtdIns(4,5)P. In PIKFYVE-dependent cells, low concentrations of WX8 specifically inhibit PIKFYVE , thereby increasing the level of its substrate PtdIns3P while suppressing PtdIns(4,5)P synthesis and inhibiting lysosome function and cell proliferation. At higher concentrations, WX8 inhibits both PIKFYVE and PIP4K2C , which amplifies these effects to further disrupt autophagy and induce cell death. WX8 did not alter PtdIns4P levels. Consequently, inhibition of PIP5K1C in WX8-resistant cells transformed them into sensitive cells, and overexpression of PIP5K1C in WX8-sensitive cells increased their resistance to WX8. This discovery suggests that PIKFYVE-dependent cancers could be identified clinically by low levels of PIP5K1C and treated with PIKFYVE inhibitors. DMSO: dimethylsulfoxide; ELISA: enzyme-linked immunosorbent assay; LC3-I: microtubule associated protein light chain 3-I; LC3-II: microtubule associated protein light chain 3-II; MS: mass spectrometry; PtdIns: phosphatidylinositol; PtdIns3P: PtdIns-3-phosphate; PtdIns4P: PtdIns-4-phosphate; PtdIns5P: PtdIns-5-phosphate; PtdIns(3,5)P: PtdIns-3,5-bisphosphate; PtdIns(4,5)P/PIP2: PtdIns-4,5-bisphosphate; PtdIns(3,4,5)P/PIP3: PtdIns-3,4,5-trisphosphate; PIKFYVE: phosphoinositide kinase, FYVE-type zinc finger containing; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PI4KA: phosphatidylinositol 4-kinase alpha; PI4KB: phosphatidylinositol 4-kinase beta; PI4K2A: phosphatidylinositol 4-kinase type 2 alpha; PI4K2B: phosphatidylinositol 4-kinase type 2 beta; PIP4K2A: phosphatidylinositol-5-phosphate 4-kinase type 2 alpha; PIP4K2B: phosphatidylinositol-5-phosphate 4-kinase type 2 beta; PIP4K2C: phosphatidylinositol-5-phosphate 4-kinase type 2 gamma; PIP5K1A: phosphatidylinositol-4-phosphate 5-kinase type 1 alpha; PIP5K1B: phosphatidylinositol-4-phosphate 5-kinase type 1 beta; PIP5K1C: phosphatidylinositol-4-phosphate 5-kinase type 1 gamma; WX8: 1H-indole-3-carbaldehyde (4-anilino-6-[4-morpholinyl]-1,3,5-triazin-2-yl)hydrazone.
Topics: Humans; 1-Phosphatidylinositol 4-Kinase; Autophagy; Phosphatidylinositol 3-Kinases; Phosphatidylinositol Phosphates; Phosphatidylinositols; Microtubule-Associated Proteins; Neoplasms; Phosphotransferases (Alcohol Group Acceptor)
PubMed: 36803256
DOI: 10.1080/15548627.2023.2182594 -
The Biochemical Journal Nov 2022In the almost 70 years since the first hints of its existence, the phosphoinositide, phosphatidyl-D-myo-inositol 4,5-bisphosphate has been found to be central in the...
In the almost 70 years since the first hints of its existence, the phosphoinositide, phosphatidyl-D-myo-inositol 4,5-bisphosphate has been found to be central in the biological regulation of plasma membrane (PM) function. Here, we provide an overview of the signaling, transport and structural roles the lipid plays at the cell surface in animal cells. These include being substrate for second messenger generation, direct modulation of receptors, control of membrane traffic, regulation of ion channels and transporters, and modulation of the cytoskeleton and cell polarity. We conclude by re-evaluating PI(4,5)P2's designation as a signaling molecule, instead proposing a cofactor role, enabling PM-selective function for many proteins.
Topics: Animals; Cell Membrane; Phosphatidylinositols; Signal Transduction; Ion Channels; Phosphatidylinositol 4,5-Diphosphate
PubMed: 36367756
DOI: 10.1042/BCJ20220445 -
Current Topics in Microbiology and... 2022This chapter is an introduction to phosphoinositide 3-kinases (PI3K), with class I PI3Ks as the central focus. First, the various PI3K isoforms in class I are presented...
This chapter is an introduction to phosphoinositide 3-kinases (PI3K), with class I PI3Ks as the central focus. First, the various PI3K isoforms in class I are presented with emphasis on their overall structure, subunits, subunit constitutive domains, domain-domain interactions, and functional relevance. This structural analysis is followed by a comprehensive history of seminal investigations into PI3K activity. Next, we highlight the divergent roles of the isoforms: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. This section details signaling pathways in which these PI3K isoforms are involved, including the key upstream regulators of PI3K activity and some downstream cellular effects. Nodes of the PI3K pathway are also presented. Inhibitors of some isoforms are discussed to give an overview of the basis of some immunotherapies that are being used to target cell signaling. Finally, the chapter ends with a discussion of the dysregulation of PI3Ks in diseases including APDS, asthma, arthritis, and oncogenic mutations.
Topics: Biology; Phosphatidylinositol 3-Kinases; Phosphatidylinositols; Protein Isoforms; Signal Transduction
PubMed: 36243838
DOI: 10.1007/978-3-031-06566-8_1 -
The Biochemical Journal Jan 2019Polyphosphoinositides (PPIs) are essential phospholipids located in the cytoplasmic leaflet of eukaryotic cell membranes. Despite contributing only a small fraction to... (Review)
Review
Polyphosphoinositides (PPIs) are essential phospholipids located in the cytoplasmic leaflet of eukaryotic cell membranes. Despite contributing only a small fraction to the bulk of cellular phospholipids, they make remarkable contributions to practically all aspects of a cell's life and death. They do so by recruiting cytoplasmic proteins/effectors or by interacting with cytoplasmic domains of membrane proteins at the membrane-cytoplasm interface to organize and mold organelle identity. The present study summarizes aspects of our current understanding concerning the metabolism, manipulation, measurement, and intimate roles these lipids play in regulating membrane homeostasis and vital cell signaling reactions in health and disease.
Topics: Animals; Cell Membrane; Humans; Membrane Proteins; Phosphatidylinositols; Signal Transduction
PubMed: 30617162
DOI: 10.1042/BCJ20180022 -
Cell Communication and Signaling : CCS Feb 2021Alzheimer's disease is one of the neurodegenerative diseases, characterized by the accumulation of abnormal protein deposits, which disrupts signal transduction in... (Review)
Review
Alzheimer's disease is one of the neurodegenerative diseases, characterized by the accumulation of abnormal protein deposits, which disrupts signal transduction in neurons and other glia cells. The pathological protein in neurodegenerative diseases, Tau and amyloid-β contribute to the disrupted microglial signaling pathways, actin cytoskeleton, and cellular receptor expression. The important secondary messenger lipids i.e., phosphatidylinositols are largely affected by protein deposits of amyloid-β in Alzheimer's disease. Phosphatidylinositols are the product of different phosphatidylinositol kinases and the state of phosphorylation at D3, D4, and D5 positions of inositol ring. Phosphatidylinositol 3,4,5-triphosphate (PI 3, 4, 5-P3) involves in phagocytic cup formation, cell polarization, whereas Phosphatidylinositol 4,5-bisphosphate (PI 4, 5-P2)-mediates the process of phagosomes formation and further its fusion with early endosome.. The necessary activation of actin-binding proteins such as Rac, WAVE complex, and ARP2/3 complex for the actin polymerization in the process of phagocytosis, migration is regulated and maintained by PI 3, 4, 5-P3 and PI 4, 5-P2. The ratio and types of fatty acid intake can influence the intracellular secondary lipid messengers along with the cellular content of phaphatidylcholine and phosphatidylethanolamine. The Amyloid-β deposits and extracellular Tau seeds disrupt phosphatidylinositides level and actin cytoskeletal network that hamper microglial-signaling pathways in AD. We hypothesize that being a lipid species intracellular levels of phosphatidylinositol would be regulated by dietary fatty acids. Further we are interested to understand phosphoinositide-based signaling cascades in phagocytosis and actin remodeling. Video Abstract.
Topics: Actins; Alzheimer Disease; Animals; Humans; Microglia; Phagocytosis; Phosphatidylinositols; Signal Transduction
PubMed: 33627135
DOI: 10.1186/s12964-021-00715-0 -
International Journal of Molecular... Apr 2020Phosphoinositides (PI) form just a minor portion of the total phospholipid content in cells but are significantly involved in cancer development and progression. In... (Review)
Review
Phosphoinositides (PI) form just a minor portion of the total phospholipid content in cells but are significantly involved in cancer development and progression. In several cancer types, phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P] and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P] play significant roles in regulating survival, proliferation, invasion, and growth of cancer cells. Phosphoinositide-specific phospholipase C (PLC) catalyze the generation of the essential second messengers diacylglycerol (DAG) and inositol 1,4,5 trisphosphate (InsP) by hydrolyzing PtdIns(4,5)P. DAG and InsP regulate Protein Kinase C (PKC) activation and the release of calcium ions (Ca) into the cytosol, respectively. This event leads to the control of several important biological processes implicated in cancer. PLCs have been extensively studied in cancer but their regulatory roles in the oncogenic process are not fully understood. This review aims to provide up-to-date knowledge on the involvement of PLCs in cancer. We focus specifically on PLCβ, PLCγ, PLCδ, and PLCε isoforms due to the numerous evidence of their involvement in various cancer types.
Topics: Animals; Diglycerides; Humans; Neoplasms; Phosphatidylinositols; Phosphoinositide Phospholipase C; Protein Kinase C; Signal Transduction
PubMed: 32276377
DOI: 10.3390/ijms21072581 -
Current Opinion in Cell Biology Aug 2021The generation of phosphoinositides (PIs) with spatial and temporal control is a key mechanism in cellular organization and signaling. The synthesis of PIs is mediated... (Review)
Review
The generation of phosphoinositides (PIs) with spatial and temporal control is a key mechanism in cellular organization and signaling. The synthesis of PIs is mediated by PI kinases, proteins that are able to phosphorylate unique substrates at specific positions on the inositol headgroup to generate signaling molecules. Phosphatidylinositol 5 phosphate 4 kinase (PIP4K) is one such lipid kinase that is able to specifically phosphorylate phosphatidylinositol 5 phosphate, the most recently discovered PI to generate the well-known and abundant PI, phosphatidylinositol 4,5 bisphosphate [PI(4,5)P]. PIP4K appears to be encoded only in metazoan genomes, and several genetic studies indicate important physiological functions for these enzymes in metabolism, immune function, and growth control. PIP4K has recently been reported to localize to multiple cellular compartments, including the nucleus, plasma membrane, endosomal systems, and autophagosome. However, the biochemical activity of these enzymes that is relevant to these physiological functions remains elusive. We review recent developments in this area and highlight emerging roles for these enzymes in cellular organization.
Topics: Animals; Cell Membrane; Endosomes; Phosphates; Phosphatidylinositols; Signal Transduction
PubMed: 33677148
DOI: 10.1016/j.ceb.2021.01.012 -
Advances in Biological Regulation Sep 2015In many human cell types, the class I phosphoinositide 3-kinases play key roles in the control of diverse cellular processes including growth, proliferation, survival... (Review)
Review
In many human cell types, the class I phosphoinositide 3-kinases play key roles in the control of diverse cellular processes including growth, proliferation, survival and polarity. This is achieved through their activation by many cell surface receptors, leading to the synthesis of the phosphoinositide lipid signal, PIP3, which in turn influences the function of numerous direct PIP3-binding proteins. Here we review PI3K pathway biology and analyse the evolutionary distribution of its components and their functions. The broad phylogenetic distribution of class I PI3Ks in metazoa, amoebozoa and choannoflagellates, implies that these enzymes evolved in single celled organisms and were later co-opted into metazoan intercellular communication. A similar distribution is evident for the AKT and Cytohesin groups of downstream PIP3-binding proteins, with other effectors and pathway components appearing to evolve later. The genomic and functional phylogeny of regulatory systems such as the PI3K pathway provides a framework to improve our understanding of the mechanisms by which key cellular processes are controlled in humans.
Topics: Animals; Evolution, Molecular; Humans; Phosphatidylinositol 3-Kinases; Phosphatidylinositol Phosphates; Phosphatidylinositols; Signal Transduction
PubMed: 26159297
DOI: 10.1016/j.jbior.2015.05.002 -
Biochimica Et Biophysica Acta.... Nov 2017Phosphatidyl-myo-inositol mannosides (PIMs) are glycolipids of unique chemical structure found in the inner and outer membranes of the cell envelope of all Mycobacterium... (Review)
Review
Phosphatidyl-myo-inositol mannosides (PIMs) are glycolipids of unique chemical structure found in the inner and outer membranes of the cell envelope of all Mycobacterium species. The PIM family of glycolipids comprises phosphatidyl-myo-inositol mono-, di-, tri-, tetra-, penta-, and hexamannosides with different degrees of acylation. PIMs are considered not only essential structural components of the cell envelope but also the precursors of lipomannan and lipoarabinomannan, two major lipoglycans implicated in host-pathogen interactions. Since the description of the complete chemical structure of PIMs, major efforts have been committed to defining the molecular bases of its biosynthetic pathway. The structural characterization of the integral membrane phosphatidyl-myo-inositol phosphate synthase (PIPS), and that of three enzymes working at the protein-membrane interface, the phosphatidyl-myo-inositol mannosyltransferases A and B, and the acyltransferase PatA, established the basis of the early steps of the PIM pathway at the molecular level. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop.
Topics: Acyltransferases; Bacterial Proteins; Cell Wall; Glycosyltransferases; Lipogenesis; Mannosyltransferases; Models, Molecular; Mycobacterium; Phosphatidylinositols; Protein Conformation; Structure-Activity Relationship; Transferases (Other Substituted Phosphate Groups)
PubMed: 27826050
DOI: 10.1016/j.bbalip.2016.11.002