Role of the ubiquitin-proteasome system in the regulation of P2Y13 receptor expression: impact on hepatic HDL uptake

Autor: Nicole Malet, Stéphanie Gayral, Camille Malaval, Michel Nauze, Laurent O. Martinez, Véronique Pons, Céline Galés, Nizar Serhan, Muriel Laffargue
Přispěvatelé: Simon, Marie Francoise, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Receptor expression
MESH: Amino Acid Sequence
Endoplasmic Reticulum
MESH: Mice
Knockout
MESH: Lipoproteins
HDL
MESH: Receptors
Purinergic P2Y12
Mice
chemistry.chemical_compound
Ubiquitin
MESH: Animals
Receptor
Mice
Knockout
MESH: Proteasome Endopeptidase Complex
Reverse cholesterol transport
Hep G2 Cells
Endocytosis
Receptors
Purinergic P2Y12
Liver
MESH: HEK293 Cells
MESH: Endocytosis
Molecular Medicine
Lipoproteins
HDL
Proteasome Endopeptidase Complex
medicine.medical_specialty
MESH: Ubiquitin
Recombinant Fusion Proteins
MESH: Hep G2 Cells
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
Biology
Cellular and Molecular Neuroscience
MESH: Mice
Inbred C57BL
MESH: Endoplasmic Reticulum
Internal medicine
medicine
MESH: Recombinant Fusion Proteins
Animals
Humans
MESH: Receptors
Purinergic P2
Amino Acid Sequence
Molecular Biology
[SDV.BC] Life Sciences [q-bio]/Cellular Biology
MESH: Mice
Pharmacology
MESH: Humans
Receptors
Purinergic P2
Cholesterol
Endoplasmic reticulum
Cell Membrane
Ubiquitination
Cell Biology
Mice
Inbred C57BL
HEK293 Cells
Endocrinology
chemistry
Proteasome
MESH: HeLa Cells
biology.protein
MESH: Ubiquitination
HeLa Cells
MESH: Liver
MESH: Cell Membrane
Zdroj: Cellular and Molecular Life Sciences
Cellular and Molecular Life Sciences, 2014, 71 (9), pp.1775-88. ⟨10.1007/s00018-013-1471-5⟩
Cellular and Molecular Life Sciences, Springer Verlag, 2014, 71 (9), pp.1775-88. ⟨10.1007/s00018-013-1471-5⟩
ISSN: 1420-682X
1420-9071
DOI: 10.1007/s00018-013-1471-5⟩
Popis: International audience; The protective effect of high density lipoproteins (HDL) against atherosclerosis is mainly attributed to their capacity to transport excess cholesterol from peripheral tissues back to the liver for further elimination into the bile, a process called reverse cholesterol transport (RCT). Recently, the importance of the P2Y13 receptor (P2Y13-R) was highlighted in HDL metabolism since HDL uptake by the liver was decreased in P2Y13-R deficient mice, which translated into impaired RCT. Here, we investigated for the first time the molecular mechanisms regulating cell surface expression of P2Y13-R. When transiently expressed, P2Y13-R was mainly detected in the endoplasmic reticulum (ER) and strongly subjected to proteasome degradation while its homologous P2Y12 receptor (P2Y12-R) was efficiently targeted to the plasma membrane. We observed an inverse correlation between cell surface expression and ubiquitination level of P2Y13-R in the ER, suggesting a close link between ubiquitination of P2Y13-R and its efficient targeting to the plasma membrane. The C-terminus tail exchange between P2Y13-R and P2Y12-R strongly restored plasma membrane expression of P2Y13-R, suggesting the involvement of the intra-cytoplasmic tail of P2Y13-R in expression defect. Accordingly, proteasomal inhibition increased plasma membrane expression of functionally active P2Y13-R in hepatocytes, and consequently stimulated P2Y13-R-mediated HDL endocytosis. Importantly, proteasomal inhibition strongly potentiated HDL hepatic uptake (>200 %) in wild-type but not in P2Y13-R-deficient mice, thus reinforcing the role of P2Y13-R expression in regulating HDL metabolism. Therefore, specific inhibition of the ubiquitin-proteasome system might be a novel powerful HDL therapy to enhance P2Y13-R expression and consequently promote the overall RCT.
Databáze: OpenAIRE
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