Polyunsaturated phospholipids facilitate membrane deformation and fission by endocytic proteins

Pinot, Mathieu; Vanni, Stefano; Pagnotta, Sophie; Lacas‐Gervais, Sandra; Payet, Laurie-Anne; Ferreira, Thierry; Gautier, Romain; Goud, Bruno; Antonny, Bruno; Barelli, Hélène

doi:10.1126/science.1255288

Cited by 319 publications

(346 citation statements)

References 49 publications

(14 reference statements)

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“…Although these data strongly implicated cholesterol as the major lipid involved in cytotoxicity, we cannot exclude that other lipids were indirectly affected in these experiments. A reduction in the cholesterol levels at the plasma membrane might reflect differences in the composition of specific lipid microdomains targeted through GP, for example, polyunsaturated phospholipids resulted in deformations of the plasma membrane 52 , and phosphatidylserine levels in the cytoplasmic leaflet might also be affected.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Ebola virus glycoprotein-mediated cytotoxicity by targeting its transmembrane domain and cholesterol

et al. 2015

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The high pathogenicity of the Ebola virus reflects multiple concurrent processes on infection. Among other important determinants, Ebola fusogenic glycoprotein (GP) has been associated with the detachment of infected cells and eventually leads to vascular leakage and haemorrhagic fever. Here we report that the membrane-anchored GP is sufficient to induce the detachment of adherent cells. The results show that the detachment induced through either full-length GP 1,2 or the subunit GP 2 depends on cholesterol and the structure of the transmembrane domain. These data reveal a novel molecular mechanism in which GP regulates Ebola virus assembly and suggest that cholesterol-reducing agents could be useful as therapeutics to counteract GP-mediated cell detachment.

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Section: Resultsmentioning

confidence: 99%

Inhibition of Ebola virus glycoprotein-mediated cytotoxicity by targeting its transmembrane domain and cholesterol

et al. 2015

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“…One possibility is that the rigid structure of SiNPs, perhaps paired with electrostatic interactions of their positively charged surface with negatively charged glycolipids lining the lumenal face of lysosomal membranes (32), may prevent membrane remodeling processes that are required for SNARE-mediated fusion with late endosomes or autophagosomes (33). Consistent with this possibility, it has been observed that membrane fission at the plasma membrane is regulated by the specific lipid environment (34). However, other mechanisms of SiNP action on lysosomal fusion cannot be ruled out.…”

Section: Discussionmentioning

confidence: 97%

Lysosomal Dysfunction Caused by Cellular Accumulation of Silica Nanoparticles

Schütz

López-Hernández

Gao

et al. 2016

Journal of Biological Chemistry

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Nanoparticles (NPs) are widely used as components of drugs or cosmetics and hold great promise for biomedicine, yet their effects on cell physiology remain poorly understood. Here we demonstrate that clathrin-independent dynamin 2-mediated caveolar uptake of surface-functionalized silica nanoparticles (SiNPs) impairs cell viability due to lysosomal dysfunction. We show that internalized SiNPs accumulate in lysosomes resulting in inhibition of autophagy-mediated protein turnover and impaired degradation of internalized epidermal growth factor, whereas endosomal recycling proceeds unperturbed. This phenotype is caused by perturbed delivery of cargo via autophagosomes and late endosomes to SiNP-filled cathepsin B/L-containing lysosomes rather than elevated lysosomal pH or altered mTOR activity. Given the importance of autophagy and lysosomal protein degradation for cellular proteostasis and clearance of aggregated proteins, these results raise the question of beneficial use of NPs in biomedicine and beyond. Nanoparticles (NPs)2 are widely used as components of drugs or cosmetics and hold great promise as tools in biomedicine to improve the detection and treatment of diseases (1). For example, nanoparticle technology has enabled improvements in cancer treatment, ranging from improved efficacy of drug delivery (2) to enhanced immunogenicity of cancer vaccines (3). Moreover, NPs are used as biosensors and biomarkers (4, 5) or for DNA/drug delivery (6). Hence, it is necessary to understand the mechanisms of interaction of NPs with living cells and tissues to assess the biological consequences associated with their application in biomedicine (7). At present, the risks associated with the biomedical application of NPs at the cellular and organismic levels remain incompletely understood (1). Among the phenotypic changes reported to be associated with the biomedical application of NPs are cellular stress responses (i.e. redox imbalance, oxidative stress), DNA damage, and altered gene expression (8,9). Which of these phenotypes can be considered a direct consequence of cellular NP association or uptake and the underlying molecular mechanisms have remained in many cases unknown.Upon cellular application, NPs initially interact with the plasma membrane, often followed by their internalization into the cell interior (10 -12) via clathrin-dependent as well as clathrin-independent endocytosis routes (i.e. via caveolae), which may require the membrane-severing GTPase dynamin (13,14). Due to the questionable specificity of many commonly used pharmacological tools toward these pathways (15) the precise mechanisms of cellular uptake of NPs often have remained elusive. After cell entry NPs are delivered to the endolysosomal system (16), where they may accumulate. Lysosomes play essential roles in cell physiology ranging from the degradation of malfunctional or aggregated proteins (e.g. via autophagy) or lipids to nutrient signaling and cellular growth control (17). For example, internalized growth factors such as EGF are sorted to la...

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“…It is conceivable that ablation of Lpcat3 may reduce the incorporation of polyunsaturated PCs in the enterocyte plasma membrane with a consequent increase in membrane rigidity, which may perturb endocytosis and protein recruitment to the plasma membrane and ultimately lead to defective lipid uptake and secretion. Indeed, intestinal cholesterol absorption is mediated by endocytosis of NPC1L1 (28), and change in the composition of polyunsaturated PCs affects the endocytosis process (29,30).…”

Section: Discussionmentioning

confidence: 99%

Small Intestine but Not Liver Lysophosphatidylcholine Acyltransferase 3 (Lpcat3) Deficiency Has a Dominant Effect on Plasma Lipid Metabolism

Kabir

Bui

et al. 2016

Journal of Biological Chemistry

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Lysophosphatidylcholine acyltransferase 3 (Lpcat3) is involved in phosphatidylcholine remodeling in the small intestine and liver. We investigated lipid metabolism in inducible intestine-specific and liver-specific Lpcat3 gene knock-out mice. We produced Lpcat3-Flox/villin-Cre-ER T2 mice, which were treated with tamoxifen (at days 1, 3, 5, and 7), to delete Lpcat3 specifically in the small intestine. At day 9 after the treatment, we found that Lpcat3 deficiency in enterocytes significantly reduced polyunsaturated phosphatidylcholines in the enterocyte plasma membrane and reduced Niemann-Pick C1-like 1 (NPC1L1), CD36, ATP-binding cassette transporter 1 (ABCA1), and ABCG8 levels on the membrane, thus significantly reducing lipid absorption, cholesterol secretion through apoB-dependent and apoB-independent pathways, and plasma triglyceride, cholesterol, and phospholipid levels, as well as body weight. Moreover, Lpcat3 deficiency does not cause significant lipid accumulation in the small intestine. We also utilized adenovirus-associated virus-Cre to deplete Lpcat3 in the liver. We found that liver deficiency only reduces plasma triglyceride levels but not other lipid levels. Furthermore, there is no significant lipid accumulation in the liver. Importantly, small intestine Lpcat3 deficiency has a much bigger effect on plasma lipid levels than that of liver deficiency. Thus, inhibition of small intestine Lpcat3 might constitute a novel approach for treating hyperlipidemia.The majority of lipids on the cell membrane as well as the plasma lipoproteins are phospholipids, in particular phosphatidylcholines (PCs) 2 (1, 2). Monounsaturated and saturated fatty acids are usually esterified at the sn-1 position of PCs, whereas polyunsaturated fatty acids are esterified at the sn-2 position (3). The asymmetric distribution of fatty acids at the sn-1 and sn-2 positions of PCs is maintained in part by a deacylationreacylation process known as the Lands cycle or PC remodeling (3, 4). One key enzyme in this remodeling is lysophosphatidylcholine acyltransferase (Lpcat), which utilizes lyso-PC and polyunsaturated acyl-CoA to produce sn-2 polyunsaturated PCs. There are four isoforms of this enzyme (5), and Lpcat3 is the major isoform in the small intestine and liver (6 -8).Lpcat3 is one of the downstream targets of liver X receptor (8) and peroxisome proliferator-activated receptor ␣ (6). Acute knockdown of Lpcat3 expression in the liver of genetically obese mice exacerbates lipid-induced endoplasmic reticulum (ER) stress (8). Moreover, global Lpcat3 knock-out (KO) mice exhibit neonatal lethality and have an abnormal small intestine (9, 10). Liver-specific deletion of Lpcat3 has no effect on ER stress but results in a reduction of plasma triglycerides and induction of hepatosteatosis under high fat feeding conditions (9). Because of neonatal lethality (non-inducible approach was utilized), only 1-week-old newborns were analyzed for the impact of intestine-specific Lpcat3 deficiency on lipid metabolism (9). Very recently, we found that...

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Polyunsaturated phospholipids facilitate membrane deformation and fission by endocytic proteins

Cited by 319 publications

References 49 publications

Inhibition of Ebola virus glycoprotein-mediated cytotoxicity by targeting its transmembrane domain and cholesterol

Inhibition of Ebola virus glycoprotein-mediated cytotoxicity by targeting its transmembrane domain and cholesterol

Lysosomal Dysfunction Caused by Cellular Accumulation of Silica Nanoparticles

Small Intestine but Not Liver Lysophosphatidylcholine Acyltransferase 3 (Lpcat3) Deficiency Has a Dominant Effect on Plasma Lipid Metabolism

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