The Deubiquitylase USP2 Regulates the LDLR Pathway by Counteracting the E3-Ubiquitin Ligase IDOL

The low-density lipoprotein (LDL) receptor (LDLR) is a central determinant of circulating LDL-cholesterol and as such subject to tight regulation. Recent studies and genetic evidence implicate the inducible degrader of the LDLR (IDOL) as a regulator of LDLR abundance and of circulating levels of LDL...

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Veröffentlicht in:Circulation research Jg. 118; H. 3; S. 410 - 419
Hauptverfasser: Nelson, Jessica Kristine, Sorrentino, Vincenzo, Avagliano Trezza, Rossella, Heride, Claire, Urbe, Sylvie, Distel, Ben, Zelcer, Noam
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 05.02.2016
Schlagworte:
Animals
Cholesterol, LDL - metabolism
Endopeptidases - genetics
Endopeptidases - metabolism
Enzyme Stability
HEK293 Cells
HeLa Cells
Hep G2 Cells
Humans
Mice, Knockout
Multienzyme Complexes
Protein Binding
Proteolysis
Receptors, LDL - genetics
Receptors, LDL - metabolism
RNA Interference
Transfection
Ubiquitin-Protein Ligases - deficiency
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
E3 ubiquitin ligase
LDL cholesterol
MYLIP/IDOL
ubiquitin
LDL receptors
USP2
ISSN:1524-4571
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Zusammenfassung:The low-density lipoprotein (LDL) receptor (LDLR) is a central determinant of circulating LDL-cholesterol and as such subject to tight regulation. Recent studies and genetic evidence implicate the inducible degrader of the LDLR (IDOL) as a regulator of LDLR abundance and of circulating levels of LDL-cholesterol in humans. Acting as an E3-ubiquitin ligase, IDOL promotes ubiquitylation and subsequent lysosomal degradation of the LDLR. Consequently, inhibition of IDOL-mediated degradation of the LDLR represents a potential strategy to increase hepatic LDL-cholesterol clearance. To establish whether deubiquitylases counteract IDOL-mediated ubiquitylation and degradation of the LDLR. Using a genetic screening approach, we identify the ubiquitin-specific protease 2 (USP2) as a post-transcriptional regulator of IDOL-mediated LDLR degradation. We demonstrate that both USP2 isoforms, USP2-69 and USP2-45, interact with IDOL and promote its deubiquitylation. IDOL deubiquitylation requires USP2 enzymatic activity and leads to a marked stabilization of IDOL protein. Paradoxically, this also markedly attenuates IDOL-mediated degradation of the LDLR and the ability of IDOL to limit LDL uptake into cells. Conversely, loss of USP2 reduces LDLR protein in an IDOL-dependent manner and limits LDL uptake. We identify a tri-partite complex encompassing IDOL, USP2, and LDLR and demonstrate that in this context USP2 promotes deubiquitylation of the LDLR and prevents its degradation. Our findings identify USP2 as a novel regulator of lipoprotein clearance owing to its ability to control ubiquitylation-dependent degradation of the LDLR by IDOL.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:1524-4571
DOI:10.1161/CIRCRESAHA.115.307298