Palmitoylation of the P2X7 receptor, an ATP‐gated channel, controls its expression and association with lipid rafts

Gonnord, Pauline; Delarasse, Cécile; Auger, Rodolphe; Benihoud, Karim; Prigent, Magali; Cuif, Marie-Hélène; Lamaze, Christophe; Kanellopoulos, Jean

doi:10.1096/fj.08-114637

Cited by 120 publications

(124 citation statements)

References 55 publications

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“…This inhibition was not complete, however, suggesting that P2X7R may be only partially located in lipid microdomains ( Fig. 3 and unpublished data), which corroborates with published findings [27,88]. P2X7R has been shown to be at least partially localized to the lipid raft fraction in T cells, and the authors suggested that lipid raft localization facilitated ADP-ribosylation of P2X7R [89].…”

Section: Lipid Pathways and The P2x7 Receptor In The Immune Systemsupporting

confidence: 89%

“…Structural analysis of the P2X7R-PIP 2 binding motif (R385-K395) [59] reveals that this motif is close to the first cysteine-palmitoylated group found in the C terminus of P2X7R. These modified residues are associated with P2X7R membrane localization [88]. The cysteinepalmitoylated group could potentially anchor P2X7R in lipid rafts, concurrently facilitating an interaction between P2X7R and PIP 2 .…”

Section: Future Perspectivesmentioning

confidence: 96%

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Lipid metabolism modulation by the P2X7 receptor in the immune system and during the course of infection: new insights into the old view

Costa-Junior

Marques-da-Silva

Vieira

et al. 2011

Purinergic Signalling

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For decades, scientists have described numerous protein pathways and functions. Much of a protein's function depends on its interactions with different partners, and those partners can change depending on the cell type or system. The P2X7 receptor (P2X7R) is one such multifunctional protein that is related to multiple partners and signaling pathways. The relationship between P2X7R and different enzymes involved in lipid metabolism represents a relatively new field in P2X7R research. This field of research began in epithelial cells and currently includes immune and nervous cells. The P2X7R-lipid metabolism pathway is related to many biological functions of P2X7R, such as cell death and pathogen clearance, and this signaling pathway may be involved in many functions that are dependent on bioactive lipids. In the present review, we will attempt to summarize data related to the P2X7R-lipid metabolism pathway, focusing on signaling pathways and their biological relevance to the immune system and infection.

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Section: Lipid Pathways and The P2x7 Receptor In The Immune Systemsupporting

confidence: 89%

Section: Future Perspectivesmentioning

confidence: 96%

Lipid metabolism modulation by the P2X7 receptor in the immune system and during the course of infection: new insights into the old view

Costa-Junior

Marques-da-Silva

Vieira

et al. 2011

Purinergic Signalling

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“…This phenotype resembles that of HEK-293 cells with P2X7 activation [39]. In fact, the activation of P2X7 can lead to different phenotypes, such as membrane blebbing and cell death by apoptosis or lysis/necrosis, depending on the cell type [41]. Taken together, there is still a possibility that P2 receptors are involved in ETX-induced death in MDCK cells and other cell types.…”

Section: Discussionmentioning

confidence: 94%

Hemolysis in human erythrocytes by Clostridium perfringens epsilon toxin requires activation of P2 receptors

et al. 2018

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Epsilon-toxin (ETX) is produced by types B and D strains of Clostridium perfringens, which cause fatal enterotoxaemia in sheep, goats and cattle. Previous studies showed that only a restricted number of cell lines are sensitive to ETX and ETX-induced hemolysis has not previously been reported. In this study, the hemolytic ability of ETX was examined using erythrocytes from 10 species including murine, rabbit, sheep, monkey and human. We found that ETX caused hemolysis in human erythrocytes (HC50 = 0.2 μM) but not erythrocytes from the other test species. Moreover, the mechanism of ETX-induced hemolysis was further explored. Recent studies showed that some bacterial toxins induce hemolysis through purinergic receptor (P2) activation. Hence, the function of purinergic receptors in ETX-induced hemolysis was tested, and we found that the non-selective P2 receptor antagonists PPADS inhibited ETX-induced lysis of human erythrocytes in a concentration-dependent manner, indicating that ETX-induced hemolysis requires activation of purinergic receptors. P2 receptors comprise seven P2X (P2X1–7) and eight P2Y (P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11–P2Y14) receptor subtypes. The pattern of responsiveness to more selective P2-antagonists implies that both P2Y13 and P2X7 receptors are involved in ETX-induced hemolysis in human species. Furthermore, we demonstrated that extracellular ATP is likely not involved in ETX-induced hemolysis and the activation of P2 receptors. These findings clarified the mechanism of ETX-induced hemolysis and provided new insight into the activities and ETX mode of action.

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“…MVs are shed by microglia upon ATP activation 27 and originate from lipid rafts, 28 where the ATP receptor P2X 7 is localized. 29 Shed MVs selectively accumulate various cellular components, including soluble and integral proteins, lipids and nucleic acids and their composition reflects the activation state of donor microglia. Notably, microglia-derived MVs in the cerebrospinal fluid (CSF) have been recently identified as a novel biomarker of brain inflammation in humans.…”

mentioning

confidence: 99%

Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles

et al. 2013

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Alzheimer's disease (AD) is characterized by extracellular amyloid-b (Ab) deposition, which activates microglia, induces neuroinflammation and drives neurodegeneration. Recent evidence indicates that soluble pre-fibrillar Ab species, rather than insoluble fibrils, are the most toxic forms of Ab. Preventing soluble Ab formation represents, therefore, a major goal in AD. We investigated whether microvesicles (MVs) released extracellularly by reactive microglia may contribute to AD degeneration. We found that production of myeloid MVs, likely of microglial origin, is strikingly high in AD patients and in subjects with mild cognitive impairment and that AD MVs are toxic for cultured neurons. The mechanism responsible for MV neurotoxicity was defined in vitro using MVs produced by primary microglia. We demonstrated that neurotoxicity of MVs results from (i) the capability of MV lipids to promote formation of soluble Ab species from extracellular insoluble aggregates and (ii) from the presence of neurotoxic Ab forms trafficked to MVs after Ab internalization into microglia. MV neurotoxicity was neutralized by the Ab-interacting protein PrP and anti-Ab antibodies, which prevented binding to neurons of neurotoxic soluble Ab species. This study identifies microglia-derived MVs as a novel mechanism by which microglia participate in AD degeneration, and suggest new therapeutic strategies for the treatment of the disease. Cell Death and Differentiation (2014) 21, 582-593; doi:10.1038/cdd.2013.180; published online 13 December 2013Alzheimer's disease (AD) is the major cause of dementia in humans. Neuronal loss and cognitive decline occurring in AD patients are traditionally linked to the accumulation in the brain of extracellular plaques consisting of short amyloid-b (Ab) peptides of 39-42 amino acids, generated by amyloidogenic cleavage of the amyloid precursor protein. 1 Among Ab peptides, Ab 1-42 and pyroglutamate-modified Ab very rapidly aggregate and initiate the complex multistep process that leads to mature fibrils and plaque. 2,3 Although association of amyloid plaques with AD has long been assumed, Ab load does not correlate with neuronal loss 4,5 and high plaque burden does not necessarily lead to dementia in humans. 6,7 Accordingly, recent evidence clearly showed that the amyloid load reaches a plateau early after the onset of clinical symptoms in AD patients 8 and does not substantially increase in size during clinical progression. 9 These observations agree with the current view that small, soluble pre-fibrillar Ab species, rather than plaques formed by insoluble Ab fibrils, are the most toxic forms of Ab. 10 These cause synaptic dysfunction and spine loss, and correlate most closely with the severity of human AD. 5,8,11 Recent biochemical studies indicated that natural sphingolipids and gangliosides, whose metabolism has been shown to be altered in AD patients, 12 destabilize and rapidly resolubilize long Ab fibrils to neurotoxic species. 13 These studies also showed that phospholipids stabilize toxic oligomers...

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Palmitoylation of the P2X7 receptor, an ATP‐gated channel, controls its expression and association with lipid rafts

Cited by 120 publications

References 55 publications

Lipid metabolism modulation by the P2X7 receptor in the immune system and during the course of infection: new insights into the old view

Lipid metabolism modulation by the P2X7 receptor in the immune system and during the course of infection: new insights into the old view

Hemolysis in human erythrocytes by Clostridium perfringens epsilon toxin requires activation of P2 receptors

Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles

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