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Current Opinion in Cell Biology Jun 2024Phosphoinositides broadly impact membrane dynamics, signal transduction and cellular physiology. The orchestration of signaling complexity by this seemingly simple... (Review)
Review
Phosphoinositides broadly impact membrane dynamics, signal transduction and cellular physiology. The orchestration of signaling complexity by this seemingly simple metabolic pathway remains an open question. It is increasingly evident that comprehending the complexity of the phosphoinositides metabolic network requires a systems view based on nonlinear dynamics, where the products of metabolism can either positively or negatively modulate enzymatic function. These feedback and feedforward loops may be paradoxical, leading to counterintuitive effects. In this review, we introduce the framework of nonlinear dynamics, emphasizing distinct dynamical regimes such as the excitable state, oscillations, and mixed-mode oscillations-all of which have been experimentally observed in phosphoinositide metabolisms. We delve into how these dynamical behaviors arise from one or multiple network motifs, including positive and negative feedback loops, coherent and incoherent feedforward loops. We explore the current understanding of the molecular circuits responsible for these behaviors. While mapping these circuits presents both conceptual and experimental challenges, redefining cellular behavior based on dynamical state, lipid fluxes, time delay, and network topology is likely essential for a comprehensive understanding of this fundamental metabolic network.
Topics: Phosphatidylinositols; Humans; Animals; Nonlinear Dynamics; Signal Transduction; Metabolic Networks and Pathways; Models, Biological
PubMed: 38797149
DOI: 10.1016/j.ceb.2024.102373 -
The Journal of Cell Biology Aug 2023The maintenance of plasma membrane integrity and a capacity for efficiently repairing damaged membranes are essential for cell survival. Large-scale wounding depletes...
The maintenance of plasma membrane integrity and a capacity for efficiently repairing damaged membranes are essential for cell survival. Large-scale wounding depletes various membrane components at the wound sites, including phosphatidylinositols, yet little is known about how phosphatidylinositols are generated after depletion. Here, working with our in vivo C. elegans epidermal cell wounding model, we discovered phosphatidylinositol 4-phosphate (PtdIns4P) accumulation and local phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] generation at the wound site. We found that PtdIns(4,5)P2 generation depends on the delivery of PtdIns4P, PI4K, and PI4P 5-kinase PPK-1. In addition, we show that wounding triggers enrichment of the Golgi membrane to the wound site, and that is required for membrane repair. Moreover, genetic and pharmacological inhibitor experiments support that the Golgi membrane provides the PtdIns4P for PtdIns(4,5)P2 generation at the wounds. Our findings demonstrate how the Golgi apparatus facilitates membrane repair in response to wounding and offers a valuable perspective on cellular survival mechanisms upon mechanical stress in a physiological context.
Topics: Animals; Caenorhabditis elegans; Cell Membrane; Golgi Apparatus; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Stress, Mechanical
PubMed: 37158801
DOI: 10.1083/jcb.202303017 -
Developmental Cell Jul 2022Focal adhesions are multifunctional organelles that couple cell-matrix adhesion to cytoskeletal force transmission and signaling and to steer cell migration and...
Focal adhesions are multifunctional organelles that couple cell-matrix adhesion to cytoskeletal force transmission and signaling and to steer cell migration and collective cell behavior. Whereas proteomic changes at focal adhesions are well understood, little is known about signaling lipids in focal adhesion dynamics. Through the characterization of cells from mice with a kinase-inactivating point mutation in the class II PI3K-C2β, we find that generation of the phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P) membrane lipid promotes focal adhesion disassembly in response to changing environmental conditions. We show that reduced growth factor signaling sensed by protein kinase N, an mTORC2 target and effector of RhoA, synergizes with the adhesion disassembly factor DEPDC1B to induce local synthesis of PtdIns(3,4)P by PI3K-C2β. PtdIns(3,4)P then promotes turnover of RhoA-dependent stress fibers by recruiting the PtdIns(3,4)P-dependent RhoA-GTPase-activating protein ARAP3. Our findings uncover a pathway by which cessation of growth factor signaling facilitates cell-matrix adhesion disassembly via a phosphoinositide lipid switch.
Topics: Animals; Cell Adhesion; Focal Adhesions; Mice; Phosphatidylinositol 3-Kinases; Phosphatidylinositol Phosphates; Phosphatidylinositols; Proteomics
PubMed: 35809565
DOI: 10.1016/j.devcel.2022.06.011 -
Development (Cambridge, England) Jun 2016The membranes of eukaryotic cells create hydrophobic barriers that control substance and information exchange between the inside and outside of cells and between... (Review)
Review
The membranes of eukaryotic cells create hydrophobic barriers that control substance and information exchange between the inside and outside of cells and between cellular compartments. Besides their roles as membrane building blocks, some membrane lipids, such as phosphoinositides (PIs), also exert regulatory effects. Indeed, emerging evidence indicates that PIs play crucial roles in controlling polarity and growth in plants. Here, I highlight the key roles of PIs as important regulatory membrane lipids in plant development and function.
Topics: Membrane Microdomains; Models, Biological; Phosphatidylinositols; Plant Development; Plants; Signal Transduction
PubMed: 27302395
DOI: 10.1242/dev.136432 -
Current Opinion in Cell Biology Aug 2023Lipid phosphoinositides are master regulators of multiple cellular functions. Misregulation of the activity of the lipid kinases that generate phosphoinositides is... (Review)
Review
Lipid phosphoinositides are master regulators of multiple cellular functions. Misregulation of the activity of the lipid kinases that generate phosphoinositides is causative of human diseases, including cancer, neurodegeneration, developmental disorders, immunodeficiencies, and inflammatory disease. This review will present a summary of recent discoveries on the roles of two phosphoinositide kinases (PI4KA and PIKfyve), which have emerged as targets for therapeutic intervention. Phosphatidylinositol 4-kinase alpha (PI4KA) generates PI4P at the plasma membrane and PIKfyve generates PI(3,5)P at endo-lysosomal membranes. Both of these enzymes exist as multi-protein mega complexes that are under myriad levels of regulation. Human disease can be caused by either loss or gain-of-function of these complexes, so understanding how they are regulated will be essential in the design of therapeutics. We will summarize insight into how these enzymes are regulated by their protein-binding partners, with a major focus on the unanswered questions of how their activity is controlled.
Topics: Humans; Cell Membrane; Lysosomes; Phosphatidylinositol 3-Kinases; Phosphatidylinositols; Signal Transduction
PubMed: 37453227
DOI: 10.1016/j.ceb.2023.102207 -
Antiviral Research May 2023Phosphatidylinositol lipids play vital roles in lipid signal transduction, membrane recognition, vesicle transport, and viral replication. Previous studies have revealed...
Phosphatidylinositol lipids play vital roles in lipid signal transduction, membrane recognition, vesicle transport, and viral replication. Previous studies have revealed that SAC1-like phosphatidylinositol phosphatase (SACM1L/SAC1), which uses phosphatidylinositol-4-phosphate (PI4P) as its substrate, greatly affects the replication of certain bacteria and viruses in vitro. However, it remains unclear whether and how SAC1 modulates hepatitis B virus (HBV) replication in vitro and in vivo. In the present study, we observed that SAC1 silencing significantly increased HBV DNA replication, subviral particle (SVP) expression, and secretion of HBV virions, whereas SAC1 overexpression exerted the opposite effects. Moreover, SAC1 overexpression inhibited HBV DNA replication and SVP expression in a hydrodynamic injection-based HBV-persistent replicating mouse model. Mechanistically, SAC1 silencing increased the number of HBV-containing autophagosomes as well as PI4P levels on the autophagosome membrane. Moreover, SAC1 silencing blocked autophagosome-lysosome fusion by inhibiting the interaction between synaptosomal-associated protein 29 and vesicle-associated membrane protein 8. Collectively, our data indicate that SAC1 significantly inhibits HBV replication by promoting the autophagic degradation of HBV virions. Our findings support that SAC1-mediated phospholipid metabolism greatly modulates certain steps of the HBV life-cycle and provide a new theoretical basis for antiviral therapy.
Topics: Animals; Mice; Hepatitis B virus; Virus Replication; Hepatitis B; Phosphatidylinositols; Virion; Phosphoric Monoester Hydrolases
PubMed: 37068596
DOI: 10.1016/j.antiviral.2023.105601 -
Bioorganic & Medicinal Chemistry Oct 2023Phosphatidylinositol transfer proteins (PITPs) are ubiquitous in eukaryotes and are involved in the regulation of phospholipid metabolism, membrane trafficking, and...
Phosphatidylinositol transfer proteins (PITPs) are ubiquitous in eukaryotes and are involved in the regulation of phospholipid metabolism, membrane trafficking, and signal transduction. Sec14 is a yeast PITP that has been shown to transfer phosphatidylinositol (PI) or phosphatidylcholine (PC) from the endoplasmic reticulum to the Golgi. It is now believed that Sec14 may play a greater role than just shuttling PI and PC throughout the cell. Genetic evidence suggests that retrieval of membrane-bound PI by Sec14 also manages to present PI to the phosphatidylinositol-4-kinase, Pik1, to generate phosphatidylinositol-4-phosphate, PI(4)P. To test this hypothetical model, we designed a photocleavable bolalipid to span the entire membrane, having one phosphatidylcholine or phosphatidylinositol headgroup on each leaflet connected by a photocleavable diacid. Sec14 should not be able to present the bola-PI to Pik1 for phosphorylation as the head group will be difficult to lift from the bilayer as it is tethered on the opposite leaflet. After photocleavage the two halves would behave as a normal phospholipid, thus phosphorylation by Pik1 would resume. We report here the synthesis of a photocleavable bola-PC, a precursor to the desired bola-PI. The mono-photocleavable bola-PC lipid was designed to contain two glycerol molecules with choline head groups connected through a phosphodiester bond at the sn3 position. Each glycerol was acylated with palmitic acid at the sn1 position. These two glycerol moieties were then connected through their respective sn2 hydroxyls via a photocleavable dicarboxylic acid containing a nitrophenyl ethyl photolabile protecting group. The bola-PC and its precursors were found to undergo efficient photocleavage when irradiated in solution or in vesicles with 365 nm light for two minutes. Treatment of the bola-PC with a mutant phospholipase D and myo-inositol produced a mono-inositol bola-PC-PI.
Topics: Phosphatidylcholines; Glycerol; Phosphorylation; Phospholipids; Phosphatidylinositols
PubMed: 37688997
DOI: 10.1016/j.bmc.2023.117465 -
Biochimica Et Biophysica Acta Jun 2015Phosphoinositides (PIs) are minor components of cell membranes, but play key roles in cell function. Recent refinements in techniques for their detection, together with... (Review)
Review
Phosphoinositides (PIs) are minor components of cell membranes, but play key roles in cell function. Recent refinements in techniques for their detection, together with imaging methods to study their distribution and changes, have greatly facilitated the study of these lipids. Such methods have been complemented by the parallel development of techniques for the acute manipulation of their levels, which in turn allow bypassing the long-term adaptive changes implicit in genetic perturbations. Collectively, these advancements have helped elucidate the role of PIs in physiology and the impact of the dysfunction of their metabolism in disease. Combining methods for detection and manipulation enables the identification of specific roles played by each of the PIs and may eventually lead to the complete deconstruction of the PI signaling network. Here, we review current techniques used for the study and manipulation of cellular PIs and also discuss advantages and disadvantages associated with the various methods. This article is part of a Special Issue entitled Phosphoinositides.
Topics: Antibodies; Cell Membrane; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Enzyme Inhibitors; Fluorescence Resonance Energy Transfer; Gene Targeting; Humans; Microscopy; Optogenetics; Phosphatidylinositols; Phosphotransferases (Alcohol Group Acceptor); Protein Structure, Tertiary; Signal Transduction
PubMed: 25514766
DOI: 10.1016/j.bbalip.2014.12.008 -
Cell Biochemistry and Function Oct 2019Phosphoinositides are very versatile molecules with a plethora of functions such as cytokinesis, chemotaxis, cell survival, and cell death. Their functions depend on the... (Review)
Review
Phosphoinositides are very versatile molecules with a plethora of functions such as cytokinesis, chemotaxis, cell survival, and cell death. Their functions depend on the proteins with which they interact. Thus, when interacting with phospholipases, phosphatases, or kinases, they can be precursors of second messengers in different signalling pathways. They could be second messengers themselves and interact directly with other proteins to modulate their functions trough changing its localization and activity or enhancing its synthesis rate. Because they are more abundant in animal cells and their importance in diseases such as cancer has taken priority, the study of the phosphoinositides in plants has not evolved to the same extent. Nevertheless, several studies have shown the significance of these lipids in plant cells viability and environmental response. This review focuses on phosphoinositides response to abiotic and biotic stress, showing their implication in plant survival during different stages of development. SIGNIFICANCE OF THE STUDY: This review is focused on plant PIPs functions in stress, highlighting in the main differences between plant and mammal PIPs and the novel interactions that could be extrapolated to animal models to contribute in a better understanding of these pivotal molecules.
Topics: Phosphatidylinositols; Plants; Stress, Physiological
PubMed: 31478243
DOI: 10.1002/cbf.3432 -
Immunological Medicine Dec 2023Activated phosphatidyl inositol 3-kinase-delta syndrome (APDS) due to gain-of-function variant in the class IA PI3K catalytic subunit p110δ (responsible gene: PIK3CD)... (Review)
Review
Activated phosphatidyl inositol 3-kinase-delta syndrome (APDS) due to gain-of-function variant in the class IA PI3K catalytic subunit p110δ (responsible gene: PIK3CD) was described in 2013. The disease is characterized by recurrent airway infections and bronchiectasis. It is associated with hyper-IgM syndrome due to the defect of immunoglobulin class switch recombination and decreased CD27-positive memory B cells. Patients also suffered from immune dysregulations, such as lymphadenopathy, autoimmune cytopenia or enteropathy. T-cell dysfunction due to increased senescence is associated with a decrease in CD4-positive T lymphocytes and CD45RA-positive naive T lymphocytes, along with increased susceptibility to Epstein-Barr virus/cytomegalovirus infections. In 2014, loss-of-function (LOF) mutation of p85α (responsible gene: PIK3R1), a regulatory subunit of p110δ, was identified as a causative gene, followed in 2016 by the identification of the LOF mutation of PTEN, which dephosphorylates PIP3, leading to the differentiation of APDS1 (PIK3CD-GOF), APDS2 (PIK3R1-LOF) and APDS-L (PTEN-LOF). Since the pathophysiology of patients with APDS varies with a wide range of severity, it is crucial that patients receive appropriate treatment and management. Our research group created a disease outline and a diagnostic flow chart and summarized clinical information such as the severity classification of APDS and treatment options.
Topics: Humans; Immunologic Deficiency Syndromes; Phosphatidylinositol 3-Kinase; Class I Phosphatidylinositol 3-Kinases; Epstein-Barr Virus Infections; Japan; Herpesvirus 4, Human; Phosphatidylinositols
PubMed: 37178059
DOI: 10.1080/25785826.2023.2210366