Proteins involved in lipid translocation in eukaryotic cells

Devaux, Philippe F.; López‐Montero, Iván; Bryde, Susanne

doi:10.1016/j.chemphyslip.2006.02.007

Cited by 66 publications

(43 citation statements)

References 104 publications

(118 reference statements)

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“…In resting cells, most of the PS is localized on the cytosolic leaflet of the lipid bilayers, an asymmetry maintained by the activity of phospholipid translocases. 31 Both efflux and influx of PS are sensitive to sulfhydryl modification. Sulfhydryl oxidizing or crosslinking reagents activate PS efflux and inhibit the flippase activity, whereas sulfhydryl reduction activates the flippase and inhibits PS efflux.…”

Section: Introductionmentioning

confidence: 99%

Extracellular protein disulfide isomerase regulates coagulation on endothelial cells through modulation of phosphatidylserine exposure

Popescu

Lupu

2010

Blood

111

115

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Tissue factor (TF) is the cellular receptor for plasma protease factor VIIa (FVIIa), and the TF-FVIIa complex initiates coagulation in both hemostasis and thrombosis. Cell surface-exposed TF is mainly cryptic and requires activation to fully exhibit the procoagulant potential. Recently, the protein disulfide isomerase (PDI) has been hypothesized to regulate TF decryption through the redox switch of an exposed disulfide in TF extracellular domain. In this study, we analyzed PDI contribution to coagulation using an in vitro endothelial cell model. In this model, extracellular PDI is detected by imaging and flow cytometry. Inhibition of cell surface PDI induces a marked increase in TF procoagulant function, whereas exogenous addition of PDI inhibits TF decryption. The coagulant effects of PDI inhibition were sensitive to annexin V treatment, suggesting exposure of phosphatidylserine (PS), which was confirmed by prothrombinase assays and direct labeling.In contrast, exogenous PDI addition enhanced PS internalization. Analysis of fluorescent PS revealed that PDI affects both the apparent flippase and floppase activities on endothelial cells. In conclusion, we identified a new mechanism for PDI contribution to coagulation on endothelial cells, namely, the regulation of PS exposure, where PDI acts as a negative regulator of coagulation. (Blood. 2010; 116(6):993-1001) IntroductionTissue factor (TF) is a transmembrane glycoprotein that binds with high affinity to the plasma protease factor VII in either zymogen (FVII) or activated form (FVIIa). The formation of the TF-FVIIa complex is crucial for initiation of coagulation, leading to thrombin generation and fibrin formation. Although the primary role of TF-FVIIa is to maintain hemostasis after vascular injury, aberrant activation of coagulation underlies thrombosis, the major cause of mortality in most industrialized countries. 1 In physiologic conditions, initiation of coagulation is maintained silent by restricting the exposure of TF to the plasma factors. 2,3 In pathologic conditions, however, TF may become exposed on the endothelium 4,5 and on circulating monocytes. 6 At these sites, TF can initiate thrombotic events associated with sepsis, 4,7 cancer, 8,9 or atherosclerosis. 10,11 Multiple in vitro studies have indicated that most of the cell-exposed TF is "cryptic," thus not fully active toward coagulation, 12,13 and TF "decryption" has been proposed as the initial step in the activation of coagulation. 14 Although the molecular mechanisms of TF decryption are not completely understood, many of the stimuli that decrypt TF also increase the exposure of phosphatidylserine (PS), [15][16][17][18] which is known to enhance coagulation. PS-independent mechanisms of TF decryption have also been postulated, such as TF self-association, 19 association with lipid rafts, [20][21][22] and the redox switch of an exposed disulfide in the membrane proximal domain of TF. 23 Protein disulfide isomerase (PDI) is an oxidoreductase 24 localized mainly in the endoplasmic reticulum (ER...

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Section: Introductionmentioning

confidence: 99%

Extracellular protein disulfide isomerase regulates coagulation on endothelial cells through modulation of phosphatidylserine exposure

Popescu

Lupu

2010

Blood

111

115

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“…Normally PS is confined exclusively to the cytoplasmic surface of the plasma membrane (15); maintenance of this asymmetric PS distribution is because of energy (ATP)-dependent aminophospholipid translocase (APLT) responsible for the inward translocation of amino phospholipids (15,16). During apoptosis, APLT is inactivated causing egress of PS from the inner to the outer leaflet of the plasma membrane (17)(18)(19).…”

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confidence: 99%

Nitrosative Stress Inhibits the Aminophospholipid Translocase Resulting in Phosphatidylserine Externalization and Macrophage Engulfment

Tyurina

Basova

Konduru

et al. 2007

Journal of Biological Chemistry

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Macrophage recognition of apoptotic cells depends on externalization of phosphatidylserine (PS), which is normally maintained within the cytosolic leaflet of the plasma membrane by aminophospholipid translocase (APLT). APLT is sensitive to redox modifications of its -SH groups. Because activated macrophages produce reactive oxygen and nitrogen species, we hypothesized that macrophages can directly participate in apoptotic cell clearance by S-nitrosylation/oxidation and inhibition of APLT causing PS externalization. Here we report that exposure of target HL-60 cells to nitrosative stress inhibited APLT, induced PS externalization, and enhanced recognition and elimination of "nitrosatively" modified cells by RAW 264.7 macrophages. Using S-nitroso-L-cysteine-ethyl ester (SNCEE) and S-nitrosoglutathione (GSNO) that cause intracellular and extracellular trans-nitrosylation of proteins, respectively, we found that SNCEE (but not GSNO) caused significant S-nitrosylation/ oxidation of thiols in HL-60 cells. SNCEE also strongly inhibited APLT, activated scramblase, and caused PS externalization. However, SNCEE did not induce caspase activation or nuclear condensation/fragmentation suggesting that PS externalization was dissociated from the common apoptotic pathway. Dithiothreitol reversed SNCEE-induced S-nitrosylation, APLT inhibition, and PS externalization. SNCEE but not GSNO stimulated phagocytosis of HL-60 cells. Moreover, phagocytosis of target cells by lipopolysaccharide-stimulated macrophages was significantly suppressed by an NO ⅐ scavenger, DAF-2. Thus, macrophage-induced nitrosylation/oxidation plays an important role in cell clearance, and hence in the resolution of inflammation.

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“…In this phospholipid asymmetry, phosphatidylcholine (PC) 2 is predominantly distributed in the outer leaflet facing extracellular space (exoplasmic leaflet), whereas phosphatidylethanolamine (PE) and phosphatidylserine (PS) are distributed in the inner leaflet facing the cytoplasm (cytoplasmic leaflet). The type 4 subfamily of P-type ATPase (P4-ATPase) seems to play an essential role to generate, maintain, and regulate phospholipid asymmetry by working as a "flippase," which translocates aminophospholipids from the exoplasmic leaflet to the cytoplasmic one in an energy-dependent manner (1)(2)(3)(4)(5).…”

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confidence: 99%

Phospholipid Flippases Lem3p-Dnf1p and Lem3p-Dnf2p Are Involved in the Sorting of the Tryptophan Permease Tat2p in Yeast

Hachiro

Yamamoto

Nakano

et al. 2013

Journal of Biological Chemistry

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Background: Lem3p-Dnf1p and Lem3p-Dnf2p are phospholipid flippases that generate phospholipid asymmetry in yeast. Results:The tryptophan permease Tat2p is missorted from the trans-Golgi network to the vacuole in the lem3⌬ mutant. Conclusion: Phospholipid asymmetry supports plasma membrane transport of Tat2p by inhibiting its improper ubiquitination at the trans-Golgi network. Significance: Phospholipid asymmetry may be involved in proper sorting of membrane proteins.

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Proteins involved in lipid translocation in eukaryotic cells

Cited by 66 publications

References 104 publications

Extracellular protein disulfide isomerase regulates coagulation on endothelial cells through modulation of phosphatidylserine exposure

Extracellular protein disulfide isomerase regulates coagulation on endothelial cells through modulation of phosphatidylserine exposure

Nitrosative Stress Inhibits the Aminophospholipid Translocase Resulting in Phosphatidylserine Externalization and Macrophage Engulfment

Phospholipid Flippases Lem3p-Dnf1p and Lem3p-Dnf2p Are Involved in the Sorting of the Tryptophan Permease Tat2p in Yeast

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