Myriocin, an inhibitor of serine palmitoyl transferase, impairs the uptake of transferrin and low-density lipoprotein in mammalian cells

Meyer, Sybille G.E.; Wendt, Agnieszka E.; Scherer, Max; Liebisch, Gerhard; Kerkweg, Uta; Schmitz, Gerd; Groot, Herbert de

doi:10.1016/j.abb.2012.07.006

Cited by 6 publications

(7 citation statements)

References 45 publications

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“…Intriguingly, longchain sphingoid bases activate Pkh1/2 (homologs of PDK1) (54), which, in turn, phosphorylate and activate the downstream kinases Ypk1/2 (homologs of SGK1) and Pkc1, a conserved kinase cascade that controls endocytosis by phosphorylating components of the endocytic machinery (55). Reminiscent of the defect in internalization of ␣-factor phero-mone in yeast with reduced sphingoid bases because of mutations in serine palmitoyltransferase (52), myriocin, an inhibitor of serine palmitoyltransferase, impaired the uptake of transferrin and low-density lipoprotein in mammalian cells (56). It is tempting to speculate that sphingoid bases play an evolutionary conserved role in the internalization step of endocytosis.…”

Section: Discussionmentioning

confidence: 99%

Sphingosine and Sphingosine Kinase 1 Involvement in Endocytic Membrane Trafficking

Lima

Milstien

Spiegel

2017

Journal of Biological Chemistry

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The balance between cholesterol and sphingolipids within the plasma membrane has long been implicated in endocytic membrane trafficking. However, in contrast to cholesterol functions, little is still known about the roles of sphingolipids and their metabolites. Perturbing the cholesterol/sphingomyelin balance was shown to induce narrow tubular plasma membrane invaginations enriched with sphingosine kinase 1 (SphK1), the enzyme that converts the bioactive sphingolipid metabolite sphingosine to sphingosine-1-phosphate, and suggested a role for sphingosine phosphorylation in endocytic membrane trafficking. Here we show that sphingosine and sphingosine-like SphK1 inhibitors induced rapid and massive formation of vesicles in diverse cell types that accumulated as dilated late endosomes. However, much smaller vesicles were formed in SphK1-deficient cells. Moreover, inhibition or deletion of SphK1 prolonged the lifetime of sphingosine-induced vesicles. Perturbing the plasma membrane cholesterol/sphingomyelin balance abrogated vesicle formation. This massive endosomal influx was accompanied by dramatic recruitment of the intracellular SphK1 and Bin/Amphiphysin/Rvs domain-containing proteins endophilin-A2 and endophilin-B1 to enlarged endosomes and formation of highly dynamic filamentous networks containing endophilin-B1 and SphK1. Together, our results highlight the importance of sphingosine and its conversion to sphingosine-1-phosphate by SphK1 in endocytic membrane trafficking.

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Section: Discussionmentioning

confidence: 99%

Sphingosine and Sphingosine Kinase 1 Involvement in Endocytic Membrane Trafficking

Lima

Milstien

Spiegel

2017

Journal of Biological Chemistry

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“…[ 155 ] However, it has also been suggested that sphingolipid synthesis could be necessary for clathrin‐mediated endocytosis as well. [ 156 ] Similarly, a widely used stimulant for macropinocytosis, phorbol‐12‐myristate‐13‐acetate (PMA), has been shown to inhibit caveolae‐mediated endocytosis. [ 149,157 ] There also exists a possibility that the blocking of one pathway increases the uptake in other pathways from what typically occurs, producing results that do not accurately reflect normal physiologic conditions.…”

Section: Tools and Techniques To Investigate Nanoparticle Transport Pmentioning

confidence: 99%

Strategies for Delivering Nanoparticles across Tumor Blood Vessels

Sheth

Wang

Bhattacharya

et al. 2020

Adv Funct Materials

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Nanoparticle transport across tumor blood vessels is a key step in nanoparticle delivery to solid tumors. However, the specific pathways and mechanisms of this nanoparticle delivery process are not fully understood. Here, the biological and physical characteristics of the tumor vasculature and the tumor microenvironment are explored and how these features affect nanoparticle transport across tumor blood vessels is discussed. The biological and physical methods to deliver nanoparticles into tumors are reviewed and paracellular and transcellular nanoparticle transport pathways are explored. Understanding the underlying pathways and mechanisms of nanoparticle tumor delivery will inform the engineering of safer and more effective nanomedicines for clinical translation.

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“…Most studies examining the role of SLs in CME have been performed using inhibitors of SL biosynthesis (Meyer et al, 2012) or by altering levels of specific SL classes, such as SM (Shakor et al, 2011). We previously demonstrated that altering the SL acyl chain length also leads to changes in membrane biophysical properties (Silva et al, 2012), which may be one of the reasons that ceramide synthase 2 (CerS2) null mice, which are unable to synthesize very long-chain SLs (Pewzner-Jung et al, 2010a,b), displays a variety of phenotypes related to ligand and receptor internalization (Ali et al, 2013;Park et al, 2012Park et al, , 2014.…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress elicited by modifying the ceramide acyl chain length reduces the rate of clathrin-mediated endocytosis

Volpert

Ben‐Dor

Tarcic

et al. 2017

Journal of Cell Science

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Sphingolipids modulate clathrin-mediated endocytosis (CME) by altering the biophysical properties of membranes. We now examine CME in astrocytes cultured from ceramide synthase 2 (CerS2) null mice, which have an altered sphingolipid acyl chain composition. The rate of endocytosis of low-density lipoprotein and transferrin, which are internalized via CME, was reduced in CerS2 null astrocytes, although the rate of caveolin-mediated endocytosis was unaltered. Levels of clathrin heavy chain were increased, which was due to decreased levels of Hsc70 (also known as HSPA8), a protein involved in clathrin uncoating. Hsc70 levels were decreased because of lower levels of binding of Sp1 to position −68 in the Hsc70 promoter. Levels of Sp1 were downregulated due to oxidative stress, which was elevated fourfold in CerS2 null astrocytes. Furthermore, induction of oxidative stress in wild-type astrocytes decreased the rate of CME, whereas amelioration of oxidative stress in CerS2 null astrocytes reversed the decrease. Our data are consistent with the notion that sphingolipids not only change membrane biophysical properties but also that changes in their composition can result in downstream effects that indirectly impinge upon a number of cellular pathways, such as CME.

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Myriocin, an inhibitor of serine palmitoyl transferase, impairs the uptake of transferrin and low-density lipoprotein in mammalian cells

Cited by 6 publications

References 45 publications

Sphingosine and Sphingosine Kinase 1 Involvement in Endocytic Membrane Trafficking

Sphingosine and Sphingosine Kinase 1 Involvement in Endocytic Membrane Trafficking

Strategies for Delivering Nanoparticles across Tumor Blood Vessels

Oxidative stress elicited by modifying the ceramide acyl chain length reduces the rate of clathrin-mediated endocytosis

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