Platelet membrane phospholipid asymmetry: from the characterization of a scramblase activity to the identification of an essential protein mutated in Scott syndrome

Lhermusier, Thibault; Chap, Hugues; Payrastre, Bernard

doi:10.1111/j.1538-7836.2011.04478.x

Cited by 156 publications

(134 citation statements)

References 85 publications

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“…[12][13][14]39 To date, platelets had to be stimulated simultaneously with extremely high doses of multiple platelet agonists to induce marginal levels of PS exposure and microvesiculation. Here we show that platelets become potently procoagulant by releasing MVs with high levels of exposed PS when stimulated with low doses of physiological agonists, but only in the presence of physiological levels of shear found in flowing blood.…”

Section: Discussionmentioning

confidence: 99%

Agonist-induced platelet procoagulant activity requires shear and a Rac1-dependent signaling mechanism

Delaney

Liu

Kim

et al. 2014

Blood

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• Physiological shear induces membrane scrambling and microvesiculation in agoniststimulated platelets.• Rac1 plays a general role in the platelet procoagulant response to shear and is important for coagulation in vitro and in vivo.Activated platelets facilitate blood coagulation by exposing phosphatidylserine (PS) and releasing microvesicles (MVs). However, the potent physiological agonists thrombin and collagen poorly induce PS exposure when a single agonist is used. To obtain a greater procoagulant response, thrombin is commonly used in combination with glycoprotein VI agonists. However, even under these conditions, only a percentage of platelets express procoagulant activity. To date, it remains unclear why platelets poorly expose PS even when stimulated with multiple agonists and what the signaling pathways are of soluble agonistinduced platelet procoagulant activity. Here we show that physiological levels of shear present in blood significantly enhance agonist-induced platelet PS exposure and MV release, enabling low doses of a single agonist to induce full-scale platelet procoagulant activity. PS exposed on the platelet surface was immediately released as MVs, revealing a tight coupling between the 2 processes under shear. Using platelet-specific Rac1 2/2 mice, we discovered that Rac1 plays a common role in mediating the low-dose agonist-induced procoagulant response independent of platelet aggregation, secretion, and the apoptosis pathway. Platelet-specific Rac1 function was not only important for coagulation in vitro but also for fibrin accumulation in vivo following laser-induced arteriolar injury. (Blood. 2014;124(12):1957-1967

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Section: Discussionmentioning

confidence: 99%

Agonist-induced platelet procoagulant activity requires shear and a Rac1-dependent signaling mechanism

Delaney

Liu

Kim

et al. 2014

Blood

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“…This asymmetrical distribution is disrupted in the activated platelets and apoptotic cells (3), in which the PtdSer exposed on the cell surface serves as a scaffold for blood clotting factors and as an "eat me" signal, respectively (4,5). ATP11A and ATP11C, members of the P4-type ATPase family, act as flippases at the plasma membrane in most cells (6,7).…”

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confidence: 99%

Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure

Suzuki

Imanishi

Nagata

2016

Proc. Natl. Acad. Sci. U.S.A.

108

130

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Xk-related protein (Xkr) 8, a protein carrying 10 transmembrane regions, is essential for scrambling phospholipids during apoptosis. Here, we found Xkr8 as a complex with basigin (BSG) or neuroplastin (NPTN), type I membrane proteins in the Ig superfamily. In BSG −/− NPTN −/− cells, Xkr8 localized intracellularly, and the apoptosis stimuli failed to expose phosphatidylserine, indicating that BSG and NPTN chaperone Xkr8 to the plasma membrane to execute its scrambling activity. Mutational analyses of BSG showed that the atypical glutamic acid in the transmembrane region is required for BSG's association with Xkr8. In cells exposed to apoptotic signals, Xkr8 was cleaved at the C terminus and the Xkr8/BSG complex formed a higher-order complex, likely to be a heterotetramer consisting of two molecules of Xkr8 and two molecules of BSG or NPTN, suggesting that this cleavage causes the formation of a larger complex of Xkr8-BSG/NPTN for phospholipid scrambling.phospholipid scramblase | Xkr8 | chaperone | basigin | neuroplastin P hospholipids are asymmetrically distributed in plasma membranes by flippases that actively translocate phosphatidylserine (PtdSer) and phosphatidylethanolamine from the outer to inner leaflets of the membrane (1, 2). This asymmetrical distribution is disrupted in the activated platelets and apoptotic cells (3), in which the PtdSer exposed on the cell surface serves as a scaffold for blood clotting factors and as an "eat me" signal, respectively (4, 5). ATP11A and ATP11C, members of the P4-type ATPase family, act as flippases at the plasma membrane in most cells (6, 7). Two processes, flippase inactivation and scramblase activation, must occur to disrupt the asymmetrical phospholipid distribution and expose PtdSer on the cell surface (8).Scramblases are membrane proteins that nonspecifically and bidirectionally transport phospholipids between the two plasma membrane leaflets (9). Ca 2+ -activated phospholipid scrambling is mediated by membrane proteins that belong to the transmembrane protein (TMEM)16 (also called ANO) family (8). Of 10 human TMEM16-family members, 5 are Ca 2+ -activated phospholipid scramblases at plasma membranes. TMEM16F exposes PtdSer in activated platelets and osteoblasts (10-12). The tertiary structure of fungal TMEM16 and the biochemical characterization of mouse TMEM16 family members indicate that TMEM16 forms a homodimer that directly binds Ca 2+ (13).Phospholipid scrambling and PtdSer exposure in apoptotic cells is mediated by another family of membrane proteins, the XK-related (Xkr) proteins (8). Of 10 human Xkr family members, Xkr8 (ubiquitously expressed) and Xkr4 and Xkr9 (expressed in specific tissues) are cleaved by caspase during apoptosis to expose PtdSer (14, 15), but how the cleavage activates these Xkrs to scramble phospholipids is unknown. XK, the founding member of the Xkr family, associates with Kell, a type II membrane protein (16). Whether Xkr8 and other Xkr-family members associate with other proteins has not been addressed.In this report, we found that...

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“…In particular, we and others showed that TMEM16F is ubiquitously expressed in various cells, including hematopoietic cells, and is involved in the phosphatidylserine (PS) exposure on activated platelets required for blood clotting (9,11,12). TMEM16F is expressed in osteoblasts and was recently shown to be involved in mineralized bone matrix production during skeletal development (13).…”

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confidence: 99%