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Nature Reviews. Molecular Cell Biology Dec 2022Phosphoinositides are signalling lipids derived from phosphatidylinositol, a ubiquitous phospholipid in the cytoplasmic leaflet of eukaryotic membranes. Initially... (Review)
Review
Phosphoinositides are signalling lipids derived from phosphatidylinositol, a ubiquitous phospholipid in the cytoplasmic leaflet of eukaryotic membranes. Initially discovered for their roles in cell signalling, phosphoinositides are now widely recognized as key integrators of membrane dynamics that broadly impact on all aspects of cell physiology and on disease. The past decade has witnessed a vast expansion of our knowledge of phosphoinositide biology. On the endocytic and exocytic routes, phosphoinositides direct the inward and outward flow of membrane as vesicular traffic is coupled to the conversion of phosphoinositides. Moreover, recent findings on the roles of phosphoinositides in autophagy and the endolysosomal system challenge our view of lysosome biology. The non-vesicular exchange of lipids, ions and metabolites at membrane contact sites in between organelles has also been found to depend on phosphoinositides. Here we review our current understanding of how phosphoinositides shape and direct membrane dynamics to impact on cell physiology, and provide an overview of emerging concepts in phosphoinositide regulation.
Topics: Phosphatidylinositols; Cell Membrane; Endosomes; Signal Transduction; Lysosomes
PubMed: 35589852
DOI: 10.1038/s41580-022-00490-x -
Nature Communications Oct 2023Exosomes are secreted to the extracellular milieu when multivesicular endosomes (MVEs) dock and fuse with the plasma membrane. However, MVEs are also known to fuse with...
Exosomes are secreted to the extracellular milieu when multivesicular endosomes (MVEs) dock and fuse with the plasma membrane. However, MVEs are also known to fuse with lysosomes for degradation. How MVEs are directed to the plasma membrane for exosome secretion rather than to lysosomes is unclear. Here we report that a conversion of phosphatidylinositol-3-phosphate (PI(3)P) to phosphatidylinositol-4-phosphate (PI(4)P) catalyzed sequentially by Myotubularin 1 (MTM1) and phosphatidylinositol 4-kinase type IIα (PI4KIIα) on the surface of MVEs mediates the recruitment of the exocyst complex. The exocyst then targets the MVEs to the plasma membrane for exosome secretion. We further demonstrate that disrupting PI(4)P generation or exocyst function blocked exosomal secretion of Programmed death-ligand 1 (PD-L1), a key immune checkpoint protein in tumor cells, and led to its accumulation in lysosomes. Together, our study suggests that the PI(3)P to PI(4)P conversion on MVEs and the recruitment of the exocyst direct the exocytic trafficking of MVEs for exosome secretion.
Topics: Exosomes; Endosomes; Phosphatidylinositols; Multivesicular Bodies
PubMed: 37898620
DOI: 10.1038/s41467-023-42661-0 -
Journal of Lipid Research Jan 2019Exosomes are a type of extracellular vesicle released from cells after fusion of multivesicular bodies with the plasma membrane. These vesicles are often enriched in... (Review)
Review
Exosomes are a type of extracellular vesicle released from cells after fusion of multivesicular bodies with the plasma membrane. These vesicles are often enriched in cholesterol, SM, glycosphingolipids, and phosphatidylserine. Lipids not only have a structural role in exosomal membranes but also are essential players in exosome formation and release to the extracellular environment. Our knowledge about the importance of lipids in exosome biology is increasing due to recent technological developments in lipidomics and a stronger focus on the biological functions of these molecules. Here, we review the available information about the lipid composition of exosomes. Special attention is given to ether lipids, a relatively unexplored type of lipids involved in membrane trafficking and abundant in some exosomes. Moreover, we discuss how the lipid composition of exosome preparations may provide useful information about their purity. Finally, we discuss the role of phosphoinositides, membrane phospholipids that help to regulate membrane dynamics, in exosome release and how this process may be linked to secretory autophagy. Knowledge about exosome lipid composition is important to understand the biology of these vesicles and to investigate possible medical applications.
Topics: Animals; Ether; Exosomes; Humans; Phosphatidylinositols
PubMed: 30076207
DOI: 10.1194/jlr.R084343 -
Science (New York, N.Y.) Dec 2022Cells respond to fluctuating nutrient supply by adaptive changes in organelle dynamics and in metabolism. How such changes are orchestrated on a cell-wide scale is...
Cells respond to fluctuating nutrient supply by adaptive changes in organelle dynamics and in metabolism. How such changes are orchestrated on a cell-wide scale is unknown. We show that endosomal signaling lipid turnover by MTM1, a phosphatidylinositol 3-phosphate [PI(3)P] 3-phosphatase mutated in X-linked centronuclear myopathy in humans, controls mitochondrial morphology and function by reshaping the endoplasmic reticulum (ER). Starvation-induced endosomal recruitment of MTM1 impairs PI(3)P-dependent contact formation between tubular ER membranes and early endosomes, resulting in the conversion of ER tubules into sheets, the inhibition of mitochondrial fission, and sustained oxidative metabolism. Our results unravel an important role for early endosomal lipid signaling in controlling ER shape and, thereby, mitochondrial form and function to enable cells to adapt to fluctuating nutrient environments.
Topics: Humans; Endoplasmic Reticulum; Endosomes; Mitochondria; Phosphatidylinositol Phosphates; Phosphatidylinositols; Signal Transduction; Protein Tyrosine Phosphatases, Non-Receptor; Mitochondrial Dynamics
PubMed: 36520888
DOI: 10.1126/science.abq5209 -
Cold Spring Harbor Perspectives in... Sep 2023Phosphoinositides (PIs) are phospholipids derived from phosphatidylinositol. PIs are regulated via reversible phosphorylation, which is directed by the opposing actions... (Review)
Review
Phosphoinositides (PIs) are phospholipids derived from phosphatidylinositol. PIs are regulated via reversible phosphorylation, which is directed by the opposing actions of PI kinases and phosphatases. PIs constitute a minor fraction of the total cellular lipid pool but play pleiotropic roles in multiple aspects of cell biology. Genetic mutations of PI regulatory enzymes have been identified in rare congenital developmental syndromes, including ciliopathies, and in numerous human diseases, such as cancer and metabolic and neurological disorders. Accordingly, PI regulatory enzymes have been targeted in the design of potential therapeutic interventions for human diseases. Recent advances place PIs as central regulators of membrane dynamics within functionally distinct subcellular compartments. This brief review focuses on the emerging role PIs play in regulating cell signaling within the primary cilium and in directing transfer of molecules at interorganelle membrane contact sites and identifies new roles for PIs in subcellular spaces.
Topics: Humans; Phosphatidylinositols; Signal Transduction; Phosphoric Monoester Hydrolases
PubMed: 37463718
DOI: 10.1101/cshperspect.a041406 -
Cell Research Aug 2023Migrasomes are recently discovered organelles, which are formed on the ends or branch points of retraction fibers at the trailing edge of migrating cells. Previously, we...
Migrasomes are recently discovered organelles, which are formed on the ends or branch points of retraction fibers at the trailing edge of migrating cells. Previously, we showed that recruitment of integrins to the site of migrasome formation is essential for migrasome biogenesis. In this study, we found that prior to migrasome formation, PIP5K1A, a PI4P kinase which converts PI4P into PI(4,5)P, is recruited to migrasome formation sites. The recruitment of PIP5K1A results in generation of PI(4,5)P at the migrasome formation site. Once accumulated, PI(4,5)P recruits Rab35 to the migrasome formation site by interacting with the C-terminal polybasic cluster of Rab35. We further demonstrated that active Rab35 promotes migrasome formation by recruiting and concentrating integrin α5 at migrasome formation sites, which is likely mediated by the interaction between integrin α5 and Rab35. Our study identifies the upstream signaling events orchestrating migrasome biogenesis.
Topics: Phosphatidylinositols; Integrin alpha5; Organelles; Signal Transduction; rab GTP-Binding Proteins; Phosphatidylinositol 4,5-Diphosphate
PubMed: 37142675
DOI: 10.1038/s41422-023-00811-5 -
Nature Immunology Mar 2023How lipidome changes support CD8 effector T (T) cell differentiation is not well understood. Here we show that, although naive T cells are rich in polyunsaturated...
How lipidome changes support CD8 effector T (T) cell differentiation is not well understood. Here we show that, although naive T cells are rich in polyunsaturated phosphoinositides (PIP with 3-4 double bonds), T cells have unique PIP marked by saturated fatty acyl chains (0-2 double bonds). PIP are precursors for second messengers. Polyunsaturated phosphatidylinositol bisphosphate (PIP) exclusively supported signaling immediately upon T cell antigen receptor activation. In late T cells, activity of phospholipase C-γ1, the enzyme that cleaves PIP into downstream mediators, waned, and saturated PIP became essential for sustained signaling. Saturated PIP was more rapidly converted to PIP with subsequent recruitment of phospholipase C-γ1, and loss of saturated PIP impaired T cell fitness and function, even in cells with abundant polyunsaturated PIP. Glucose was the substrate for de novo PIP synthesis, and was rapidly utilized for saturated PIP generation. Thus, separate PIP pools with distinct acyl chain compositions and metabolic dependencies drive important signaling events to initiate and then sustain effector function during CD8+ T cell differentiation.
Topics: Phosphatidylinositols; Phosphatidylinositol Phosphates; Signal Transduction; Type C Phospholipases; CD8-Positive T-Lymphocytes
PubMed: 36732424
DOI: 10.1038/s41590-023-01419-y -
Current Opinion in Cell Biology Jun 2022Phosphoinositide signaling lipids are crucial for eukaryotes and regulate many aspects of cell function. These signaling molecules are difficult to study because they... (Review)
Review
Phosphoinositide signaling lipids are crucial for eukaryotes and regulate many aspects of cell function. These signaling molecules are difficult to study because they are extremely low abundance. Here, we focus on two of the lowest abundance phosphoinositides, PI(3,5)P and PI(5)P, which play critical roles in cellular homeostasis, membrane trafficking and transcription. Their levels are tightly regulated by a protein complex that includes PIKfyve, Fig4 and Vac14. Importantly, mutations in this complex that decrease PI(3,5)P and PI(5)P are linked to human diseases, especially those of the nervous system. Paradoxically, PIKfyve inhibitors which decrease PI(3,5)P and PI(5)P, are currently being tested for some neurodegenerative diseases, as well as other diverse diseases including some cancers, and as a treatment for SARS-CoV2 infection. A more comprehensive picture of the pathways that are regulated by PIKfyve will be critical to understand the roles of PI(3,5)P and PI(5)P in normal human physiology and in disease.
Topics: Flavoproteins; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Phosphatidylinositol 3-Kinases; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phosphoric Monoester Hydrolases; RNA, Viral; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35584589
DOI: 10.1016/j.ceb.2022.102086 -
Cells Dec 2022The plasma membrane of eukaryotic cells is composed of a large number of lipid species that are laterally segregated into functional domains as well as asymmetrically... (Review)
Review
The plasma membrane of eukaryotic cells is composed of a large number of lipid species that are laterally segregated into functional domains as well as asymmetrically distributed between the outer and inner leaflets. Additionally, the spatial distribution and organization of these lipids dramatically change in response to various cellular states, such as cell division, differentiation, and apoptosis. Division of one cell into two daughter cells is one of the most fundamental requirements for the sustenance of growth in all living organisms. The successful completion of cytokinesis, the final stage of cell division, is critically dependent on the spatial distribution and organization of specific lipids. In this review, we discuss the properties of various lipid species associated with cytokinesis and the mechanisms involved in their polarization, including forward trafficking, endocytic recycling, local synthesis, and cortical flow models. The differences in lipid species requirements and distribution in mitotic vs. male meiotic cells will be discussed. We will concentrate on sphingolipids and phosphatidylinositols because their transbilayer organization and movement may be linked via the cytoskeleton and thus critically regulate various steps of cytokinesis.
Topics: Male; Humans; Cytokinesis; Cell Division; Cell Membrane; Biological Transport; Phosphatidylinositols
PubMed: 36552741
DOI: 10.3390/cells11243977 -
International Journal of Molecular... Apr 2023Phafins are PH (Pleckstrin Homology) and FYVE (Fab1, YOTB, Vac1, and EEA1) domain-containing proteins. The Phafin protein family is classified into two groups based on... (Review)
Review
Phafins are PH (Pleckstrin Homology) and FYVE (Fab1, YOTB, Vac1, and EEA1) domain-containing proteins. The Phafin protein family is classified into two groups based on their sequence homology and functional similarity: Phafin1 and Phafin2. This protein family is unique because both the PH and FYVE domains bind to phosphatidylinositol 3-phosphate [PtdIns(3)P], a phosphoinositide primarily found in endosomal and lysosomal membranes. Phafin proteins act as PtdIns(3)P effectors in apoptosis, endocytic cargo trafficking, and autophagy. Additionally, Phafin2 is recruited to macropinocytic compartments through coincidence detection of PtdIns(3)P and PtdIns(4)P. Membrane-associated Phafins serve as adaptor proteins that recruit other binding partners. In addition to the phosphoinositide-binding domains, Phafin proteins present a poly aspartic acid motif that regulates membrane binding specificity. In this review, we summarize the involvement of Phafins in several cellular pathways and their potential physiological functions while highlighting the similarities and differences between Phafin1 and Phafin2. Besides, we discuss research perspectives for Phafins.
Topics: Carrier Proteins; Phosphatidylinositols; Phosphatidylinositol Phosphates; Intracellular Membranes; Apoptosis; Endosomes; Protein Binding
PubMed: 37175801
DOI: 10.3390/ijms24098096