The deubiquitylase USP2 regulates the LDLR pathway by counteracting the E3-ubiquitin ligase IDOL

Nelson, Jessica Kristine, Sorrentino, Vincenzo, Avagliano Trezza, Rossella, Heride, Claire, Urbe, Sylvie, Distel, Ben and Zelcer, Noam (2016) The deubiquitylase USP2 regulates the LDLR pathway by counteracting the E3-ubiquitin ligase IDOL. Circulation Research, 118 (3), 410-419. (doi:10.1161/CIRCRESAHA.115.307298).

Abstract

Rationale: 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.

Objective: to establish whether deubiquitylases counteract IDOL-mediated ubiquitylation and degradation of the LDLR.

Methods and results: 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.

Conclusions: 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.

This record has no associated files available for download.

Contributors

Author: Jessica Kristine Nelson

Download statistics