scholarly journals The acyltransferase LYCAT controls specific phosphoinositides and related membrane traffic

2017 ◽  
Vol 28 (1) ◽  
pp. 161-172 ◽  
Author(s):  
Leslie N. Bone ◽  
Roya M. Dayam ◽  
Minhyoung Lee ◽  
Nozomu Kono ◽  
Gregory D. Fairn ◽  
...  
Keyword(s):  
Acyl Chain ◽  
Membrane Traffic ◽  
Cell Physiology ◽  
Phosphatidylinositol Synthase ◽  
Lipid Kinases ◽  
Acyl Chains ◽  
And Function ◽  
Phosphatidylinositol 4 ◽  
Phosphatidylinositol 3

Phosphoinositides (PIPs) are key regulators of membrane traffic and signaling. The interconversion of PIPs by lipid kinases and phosphatases regulates their functionality. Phosphatidylinositol (PI) and PIPs have a unique enrichment of 1-stearoyl-2-arachidonyl acyl species; however, the regulation and function of this specific acyl profile remains poorly understood. We examined the role of the PI acyltransferase LYCAT in control of PIPs and PIP-dependent membrane traffic. LYCAT silencing selectively perturbed the levels and localization of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] and phosphatidylinositol-3-phosphate and the membrane traffic dependent on these specific PIPs but was without effect on phosphatidylinositol-4-phosphate or biosynthetic membrane traffic. The acyl profile of PI(4,5)P2 was selectively altered in LYCAT-deficient cells, whereas LYCAT localized with phosphatidylinositol synthase. We propose that LYCAT remodels the acyl chains of PI, which is then channeled into PI(4,5)P2. Our observations suggest that the PIP acyl chain profile may exert broad control of cell physiology.

scholarly journals Control Of Phosphoinositide Synthesis And Degradation By The Acyltransferase Lycat

2021 ◽  
Author(s):  
Yasmin Awadeh
Keyword(s):  
Intracellular Signaling ◽  
Critical Role ◽  
Membrane Traffic ◽  
New Information ◽  
Selective Incorporation ◽  
Lipid Kinases ◽  
Membrane Compartments ◽  
Epidermal Growth ◽  
And Function

Phosphoinositides (PIPs) are important regulators of various cellular phenomena including intracellular signaling, membrane traffic and cell migration. PIPs are formed as a result of the regulated phosphorylation of the inositol headgroup of phosphatidylinositol (PI) on specific positions by certain lipid kinases and phosphatases. It is well appreciated that the enrichment of specific PIPs, defined by inositol headgroup phosphorylation, within specific membrane compartments plays a critical role in organelle identity and membrane traffic. However, while much attention has been given to understanding of the role of inositol headgroup phosphorylation in PIP function, much less is known about the role of dynamic incorporation of specific acyl groups into these phospholipids. Importantly, PI and PIPs exhibit remarkable and unique selectivity for certain acyl groups. For example, about 45% of PIs (but not other phospholipids) are rich in 1-steroyl 2-arachidonyl. We recently identified that the possible control of the selective incorporation of steric acid at the sn-1 position is by the acyltransferase LYCAT, which controls the levels, acyl profile and function of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) (Bone et al. Mol Biol Cell 2017. 28:161-172). Here we examine how perturbation of LYCAT leads to a reduction in the levels of PI(4,5)P2 and phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3). To measure the rate of PI(4,5)P2 synthesis, we treated cells with ionomycin to first ablate this PIP, followed by washout of the drug and monitoring of rate of reappearance via localization of a fluorescent PI(4,5)P2 probe. To measure the rate of PI(4,5)P2 degradation, we arrested PI(4,5)P2 synthesis by a pharmacological inhibitor, phenylarsine oxide (PAO) and monitored the loss of cellular PI(4,5)P2. Lastly, to examine the production of PI(3,4,5)P3, we treated cells with epidermal growth factor (EGF) and monitored the production of this PIP. Together, this work provides new information about how the dynamic and selective remodeling of specific phospholipids controls their levels, localization and function.

scholarly journals Control Of Phosphoinositide Synthesis And Degradation By The Acyltransferase Lycat

2021 ◽  
Author(s):  
Yasmin Awadeh
Keyword(s):  
Intracellular Signaling ◽  
Critical Role ◽  
Membrane Traffic ◽  
New Information ◽  
Selective Incorporation ◽  
Lipid Kinases ◽  
Membrane Compartments ◽  
Epidermal Growth ◽  
And Function

Phosphoinositides (PIPs) are important regulators of various cellular phenomena including intracellular signaling, membrane traffic and cell migration. PIPs are formed as a result of the regulated phosphorylation of the inositol headgroup of phosphatidylinositol (PI) on specific positions by certain lipid kinases and phosphatases. It is well appreciated that the enrichment of specific PIPs, defined by inositol headgroup phosphorylation, within specific membrane compartments plays a critical role in organelle identity and membrane traffic. However, while much attention has been given to understanding of the role of inositol headgroup phosphorylation in PIP function, much less is known about the role of dynamic incorporation of specific acyl groups into these phospholipids. Importantly, PI and PIPs exhibit remarkable and unique selectivity for certain acyl groups. For example, about 45% of PIs (but not other phospholipids) are rich in 1-steroyl 2-arachidonyl. We recently identified that the possible control of the selective incorporation of steric acid at the sn-1 position is by the acyltransferase LYCAT, which controls the levels, acyl profile and function of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) (Bone et al. Mol Biol Cell 2017. 28:161-172). Here we examine how perturbation of LYCAT leads to a reduction in the levels of PI(4,5)P2 and phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3). To measure the rate of PI(4,5)P2 synthesis, we treated cells with ionomycin to first ablate this PIP, followed by washout of the drug and monitoring of rate of reappearance via localization of a fluorescent PI(4,5)P2 probe. To measure the rate of PI(4,5)P2 degradation, we arrested PI(4,5)P2 synthesis by a pharmacological inhibitor, phenylarsine oxide (PAO) and monitored the loss of cellular PI(4,5)P2. Lastly, to examine the production of PI(3,4,5)P3, we treated cells with epidermal growth factor (EGF) and monitored the production of this PIP. Together, this work provides new information about how the dynamic and selective remodeling of specific phospholipids controls their levels, localization and function.

scholarly journals PI(4,5)P2 controls slit diaphragm formation and endocytosis in Drosophila nephrocytes

2021 ◽  
Author(s):  
Max Gass ◽  
Sarah Borkowsky ◽  
Marie-Luise Lotz ◽  
Rita Schroeter ◽  
Pavel Nedvetsky ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Model System ◽  
Dominant Negative ◽  
Slit Diaphragm ◽  
Phosphatidylinositol 3 Kinase ◽  
Ectopic Activation ◽  
Phosphatidylinositol 4 ◽  
Asymmetrically Distributed ◽  
Phosphatidylinositol 3

Drosophila nephrocytes are an emerging model system for mammalian podocytes and podocyte-associated diseases. Like podocytes, nephrocytes exhibit characteristics of epithelial cells, but the role of phospholipids in polarization of these cells is yet unclear. In epithelia phosphatidylinositol(4,5)bisphosphate (PI(4,5)P2) and phosphatidylinositol(3,4,5)-trisphosphate (PI(3,4,5)P3) are asymmetrically distributed in the plasma membrane and determine apical-basal polarity. Here we demonstrate that both phospholipids are present in the plasma membrane of nephrocytes, but only PI(4,5)P2 accumulates at slit diaphragms. Knockdown of Skittles, a phosphatidylinositol(4)phosphate 5-kinase, which produces PI(4,5)P2, abolished slit diaphragm formation and led to strongly reduced endocytosis. Notably, reduction in PI(3,4,5)P3 by overexpression of PTEN or expression of a dominant-negative phosphatidylinositol-3-Kinase did not affect nephrocyte function, whereas enhanced formation of PI(3,4,5)P3 by constitutively active phosphatidylinositol-3-Kinase resulted in strong slit diaphragm and endocytosis defects by ectopic activation of the Akt/mTOR pathway. Thus, PI(4,5)P2 but not PI(3,4,5)P3 is essential for slit diaphragm formation and nephrocyte function. However, PI(3,4,5)P3 has to be tightly controlled to ensure nephrocyte development.

scholarly journals OGT regulates mitochondrial biogenesis and function via diabetes susceptibility gene Pdx1

2021 ◽  
Author(s):  
Ramkumar Mohan ◽  
Seokwon Jo ◽  
Amber Lockridge ◽  
Deborah A. Ferrington ◽  
Kevin Murray ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Susceptibility Gene ◽  
Mitochondrial Morphology ◽  
Cell Physiology ◽  
Β Cells ◽  
Β Cell ◽  
Atp Production ◽  
Glcnac Transferase ◽  
And Function

O-GlcNAc transferase (OGT), a nutrient-sensor sensitive to glucose flux, is highly expressed in the pancreas. However, the role of OGT in the mitochondria of β-cells is unexplored. Here, we identified the role of OGT in mitochondrial function in β-cells. Constitutive deletion of OGT (βOGTKO) or inducible ablation in mature β-cells (iβOGTKO) causes distinct effects on mitochondrial morphology and function. Islets from βOGTKO, but not iβOGTKO, mice display swollen mitochondria, reduced glucose-stimulated oxygen consumption rate, ATP production and glycolysis. Alleviating ER stress by genetic deletion of Chop did not rescue the mitochondrial dysfunction in βOGTKO mice. We identified altered islet proteome between βOGTKO and iβOGTKO mice. Pancreatic and duodenal homeobox 1 (Pdx1) was reduced in in βOGTKO islets. Pdx1 over-expression increased insulin content and improved mitochondrial morphology and function in βOGTKO islets. These data underscore the essential role of OGT in regulating β-cell mitochondrial morphology and bioenergetics. In conclusion, OGT couples nutrient signal and mitochondrial function to promote normal β-cell physiology. <br>

scholarly journals 4′-Phosphopantetheine and long acyl chain-dependent interactions are integral to human mitochondrial acyl carrier protein function

MedChemComm ◽  
2019 ◽  
Vol 10 (2) ◽  
pp. 209-220 ◽  
Author(s):  
Jaimeen D. Majmudar ◽  
Xidong Feng ◽  
Nicholas G. Fox ◽  
Joseph F. Nabhan ◽  
Theresa Towle ◽  
...  
Keyword(s):  
Protein Function ◽  
Acyl Carrier Protein ◽  
Acyl Chain ◽  
Carrier Protein ◽  
Acyl Chains

Insights into the role of 4′-PP- and long acyl chains-dependent interactions in human ACPM function.

Phosphoinositides in Constitutive Membrane Traffic

2004 ◽  
Vol 84 (3) ◽  
pp. 699-730 ◽  
Author(s):  
Michael G. Roth
Keyword(s):  
Plasma Membrane ◽  
Membrane Proteins ◽  
Membrane Traffic ◽  
Spatial Segregation ◽  
Peripheral Membrane Proteins ◽  
Transport Vesicles ◽  
Early Endosomes ◽  
Lipid Kinases ◽  
Phosphatidylinositol 4 ◽  
Different Parts

Proteins that make, consume, and bind to phosphoinositides are important for constitutive membrane traffic. Different phosphoinositides are concentrated in different parts of the central vacuolar pathway, with phosphatidylinositol 4-phosphate predominate on Golgi, phosphatidylinositol 4,5-bisphosphate predominate at the plasma membrane, phosphatidylinositol 3-phosphate the major phosphoinositide on early endosomes, and phosphatidylinositol 3,5-bisphosphate found on late endocytic organelles. This spatial segregation may be the mechanism by which the direction of membrane traffic is controlled. Phosphoinositides increase the affinity of membranes for peripheral membrane proteins that function for sorting protein cargo or for the docking and fusion of transport vesicles. This implies that constitutive membrane traffic may be regulated by the mechanisms that control the activity of the enzymes that produce and consume phosphoinositides. Although the lipid kinases and phosphatases that function in constitutive membrane traffic are beginning to be identified, their regulation is poorly understood.

scholarly journals PI(4,5)P2 Controls Slit Diaphragm Formation and Endocytosis in Drosophila Nephrocytes

2021 ◽  
Author(s):  
Maximilian Gass ◽  
Sarah Borkowsky ◽  
Marie-Luise Lotz ◽  
Rita Schröter ◽  
Pavel Nedvetsky ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Model System ◽  
Dominant Negative ◽  
Slit Diaphragm ◽  
Phosphatidylinositol 3 Kinase ◽  
Ectopic Activation ◽  
Phosphatidylinositol 4 ◽  
Asymmetrically Distributed ◽  
Phosphatidylinositol 3

Abstract Drosophila nephrocytes are an emerging model system for mammalian podocytes and podocyte-associated diseases. Like podocytes, nephrocytes exhibit characteristics of epithelial cells, but the role of phospholipids in polarization of these cells is yet unclear. In epithelia phosphatidylinositol(4,5)bisphosphate (PI(4,5)P2) and phosphatidylinositol(3,4,5)-trisphosphate (PI(3,4,5)P3) are asymmetrically distributed in the plasma membrane and determine apical-basal polarity. Here we demonstrate that both phospholipids are present in the plasma membrane of nephrocytes, but only PI(4,5)P2 accumulates at slit diaphragms. Knockdown of Skittles, a phosphatidylinositol(4)phosphate 5-kinase, which produces PI(4,5)P2, abolished slit diaphragm formation and led to strongly reduced endocytosis. Notably, reduction in PI(3,4,5)P3 by overexpression of PTEN or expression of a dominant-negative phosphatidylinositol-3-Kinase did not affect nephrocyte function, whereas enhanced formation of PI(3,4,5)P3 by constitutively active phosphatidylinositol-3-Kinase resulted in strong slit diaphragm and endocytosis defects by ectopic activation of the Akt/mTOR pathway. Thus, PI(4,5)P2 but not PI(3,4,5)P3 is essential for slit diaphragm formation and nephrocyte function. However, PI(3,4,5)P3 has to be tightly controlled to ensure nephrocyte development.

scholarly journals Schizosaccharomyces pombe Sst4p, a Conserved Vps27/Hrs Homolog, Functions Downstream of Phosphatidylinositol 3-Kinase Pik3p To Mediate Proper Spore Formation

2007 ◽  
Vol 6 (12) ◽  
pp. 2343-2353 ◽  
Author(s):  
Masayuki Onishi ◽  
Michihiro Iida ◽  
Takako Koga ◽  
Sadayuki Yamada ◽  
Aiko Hirata ◽  
...  
Keyword(s):  
Schizosaccharomyces Pombe ◽  
Fluorescent Protein ◽  
Developmental Process ◽  
Intracellular Membrane ◽  
Phosphatidylinositol 3 Kinase ◽  
Fyve Domain ◽  
Membrane Compartments ◽  
And Function ◽  
Phosphatidylinositol 3

ABSTRACT Sporulation of the fission yeast Schizosaccharomyces pombe is a developmental process that generates gametes and that includes the formation of spore envelope precursors called the forespore membranes. Assembly and development of forespore membranes require vesicular trafficking from other intracellular membrane compartments. We have shown that phosphatidylinositol 3-kinase (PtdIns 3-kinase) is required for efficient and proper development of forespore membranes. The role of a FYVE domain protein, Sst4p, a homolog of Vps27p/Hrs, as a downstream factor for PtdIns 3-kinase in sporulation was investigated. sst4Δ asci formed spores with oval-shaped morphology and with reduced viability compared to that of the wild-type spores. The extension of forespore membranes was inefficient, and bubble-like structures emerged from the leading edges of the forespore membranes. Sst4p localization was examined using fluorescent protein fusions and was found to be adjacent to the forespore membranes during sporulation. The localization and function of Sst4p were dependent on its FYVE domain and on PtdIns 3-kinase. Sst4p colocalized and interacted with Hse1p, a homolog of Saccharomyces cerevisiae Hse1p and of mammalian STAM. Mutations in all three UIM domains of the Sst4p/Hse1p complex resulted in formation of spores with abnormal morphology. These results suggest that Sst4p is a downstream factor of PtdIns 3-kinase and functions in forespore membrane formation.

scholarly journals Accessory proteins of the zDHHC family of S-acylation enzymes

2020 ◽  
Vol 133 (22) ◽  
pp. jcs251819
Author(s):  
Christine Salaun ◽  
Carolina Locatelli ◽  
Filip Zmuda ◽  
Juan Cabrera González ◽  
Luke H. Chamberlain
Keyword(s):  
Fatty Acyl ◽  
Accessory Proteins ◽  
Enzyme Substrate ◽  
Essential Components ◽  
Selenoprotein K ◽  
Acyl Chains ◽  
The Stability ◽  
And Function ◽  
Encoding Genes

ABSTRACTAlmost two decades have passed since seminal work in Saccharomyces cerevisiae identified zinc finger DHHC domain-containing (zDHHC) enzymes as S-acyltransferases. These enzymes are ubiquitous in the eukarya domain, with 23 distinct zDHHC-encoding genes in the human genome. zDHHC enzymes mediate the bulk of S-acylation (also known as palmitoylation) reactions in cells, transferring acyl chains to cysteine thiolates, and in so-doing affecting the stability, localisation and function of several thousand proteins. Studies using purified components have shown that the minimal requirements for S-acylation are an appropriate zDHHC enzyme–substrate pair and fatty acyl-CoA. However, additional proteins including GCP16 (also known as Golga7), Golga7b, huntingtin and selenoprotein K, have been suggested to regulate the activity, stability and trafficking of certain zDHHC enzymes. In this Review, we discuss the role of these accessory proteins as essential components of the cellular S-acylation system.

scholarly journals Phosphatidylinositol 4-phosphate and phosphatidylinositol 3-phosphate regulate phagolysosome biogenesis

2015 ◽  
Vol 112 (15) ◽  
pp. 4636-4641 ◽  
Author(s):  
Andreas Jeschke ◽  
Nicole Zehethofer ◽  
Buko Lindner ◽  
Jessica Krupp ◽  
Dominik Schwudke ◽  
...  
Keyword(s):  
Early Endosome ◽  
Phagosome Maturation ◽  
Phagocytic Cells ◽  
Late Endosomes ◽  
Early Endosomes ◽  
Lipid Kinases ◽  
Phosphatidylinositol 4 ◽  
Endocytic Compartments ◽  
Late Stages ◽  
Phosphatidylinositol 3

Professional phagocytic cells ingest microbial intruders by engulfing them into phagosomes, which subsequently mature into microbicidal phagolysosomes. Phagosome maturation requires sequential fusion of the phagosome with early endosomes, late endosomes, and lysosomes. Although various phosphoinositides (PIPs) have been detected on phagosomes, it remained unclear which PIPs actually govern phagosome maturation. Here, we analyzed the involvement of PIPs in fusion of phagosomes with various endocytic compartments and identified phosphatidylinositol 4-phosphate [PI(4)P], phosphatidylinositol 3-phosphate [PI(3)P], and the lipid kinases that generate these PIPs, as mediators of phagosome–lysosome fusion. Phagosome–early endosome fusion required PI(3)P, yet did not depend on PI(4)P. Thus, PI(3)P regulates phagosome maturation at early and late stages, whereas PI(4)P is selectively required late in the pathway.

Sign in / Sign up

Export Citation Format

Share Document