The LXR-IDOL axis defines a clathrin-, caveolae-, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation
The LXR-IDOL axis defines a clathrin-, caveolae-, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation
Low density lipoprotein (LDL) cholesterol is taken up into cells via clathrin-mediated endocytosis of the LDL receptor (LDLR). Following dissociation of the LDLR-LDL complex, LDL is directed to lysosomes whereas the LDLR recycles to the plasma membrane. Activation of the sterol-sensing nuclear receptors liver X receptors (LXRs) enhances degradation of the LDLR. This depends on the LXR target gene inducible degrader of the LDLR (IDOL), an E3-ubiquitin ligase that promotes ubiquitylation and lysosomal degradation of the LDLR. How ubiquitylation of the LDLR by IDOL controls its endocytic trafficking is currently unknown. Using genetic- and pharmacological-based approaches coupled to functional assessment of LDL uptake, we show that the LXR-IDOL axis targets a LDLR pool present in lipid rafts. IDOL-dependent internalization of the LDLR is independent of clathrin, caveolin, macroautophagy, and dynamin. Rather, it depends on the endocytic protein epsin. Consistent with LDLR ubiquitylation acting as a sorting signal, degradation of the receptor can be blocked by perturbing the endosomal sorting complex required for transport (ESCRT) or by USP8, a deubiquitylase implicated in sorting ubiquitylated cargo to multivesicular bodies. In summary, we provide evidence for the existence of an LXR-IDOL-mediated internalization pathway for the LDLR that is distinct from that used for lipoprotein uptake.
Caveolae/metabolism, Cells, Cultured, Clathrin/metabolism, Dynamins/metabolism, Endocytosis, HEK293 Cells, HeLa Cells, Hep G2 Cells, Humans, Liver X Receptors, Lysosomes/metabolism, Orphan Nuclear Receptors/metabolism, Receptors, LDL/metabolism, Ubiquitin-Protein Ligases/metabolism
2174-2184
Sorrentino, Vincenzo
f0cb3b5b-3a17-4ab3-ab65-180a7ee50d8a
Nelson, Jessica K.
7dc3f0c8-5a67-4467-a332-efd560a0630b
Maspero, Elena
00bc7993-5767-4b66-9cf7-dfd43234a6f0
Marques, André R.A.
442c3876-1fd2-4c44-99ba-8f0ac3ed6307
Scheer, Lilith
208aa2a0-837f-4d98-bcb4-f91261a57ef7
Polo, Simona
a5fdd173-8793-4e34-a3fd-2883a11b8b2c
Zelcer, Noam
c5eff664-b107-4a7c-9823-11ccb8149fbc
August 2013
Sorrentino, Vincenzo
f0cb3b5b-3a17-4ab3-ab65-180a7ee50d8a
Nelson, Jessica K.
7dc3f0c8-5a67-4467-a332-efd560a0630b
Maspero, Elena
00bc7993-5767-4b66-9cf7-dfd43234a6f0
Marques, André R.A.
442c3876-1fd2-4c44-99ba-8f0ac3ed6307
Scheer, Lilith
208aa2a0-837f-4d98-bcb4-f91261a57ef7
Polo, Simona
a5fdd173-8793-4e34-a3fd-2883a11b8b2c
Zelcer, Noam
c5eff664-b107-4a7c-9823-11ccb8149fbc
Sorrentino, Vincenzo, Nelson, Jessica K., Maspero, Elena, Marques, André R.A., Scheer, Lilith, Polo, Simona and Zelcer, Noam
(2013)
The LXR-IDOL axis defines a clathrin-, caveolae-, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation.
Journal of Lipid Research, 54 (8), .
(doi:10.1194/jlr.M037713).
Abstract
Low density lipoprotein (LDL) cholesterol is taken up into cells via clathrin-mediated endocytosis of the LDL receptor (LDLR). Following dissociation of the LDLR-LDL complex, LDL is directed to lysosomes whereas the LDLR recycles to the plasma membrane. Activation of the sterol-sensing nuclear receptors liver X receptors (LXRs) enhances degradation of the LDLR. This depends on the LXR target gene inducible degrader of the LDLR (IDOL), an E3-ubiquitin ligase that promotes ubiquitylation and lysosomal degradation of the LDLR. How ubiquitylation of the LDLR by IDOL controls its endocytic trafficking is currently unknown. Using genetic- and pharmacological-based approaches coupled to functional assessment of LDL uptake, we show that the LXR-IDOL axis targets a LDLR pool present in lipid rafts. IDOL-dependent internalization of the LDLR is independent of clathrin, caveolin, macroautophagy, and dynamin. Rather, it depends on the endocytic protein epsin. Consistent with LDLR ubiquitylation acting as a sorting signal, degradation of the receptor can be blocked by perturbing the endosomal sorting complex required for transport (ESCRT) or by USP8, a deubiquitylase implicated in sorting ubiquitylated cargo to multivesicular bodies. In summary, we provide evidence for the existence of an LXR-IDOL-mediated internalization pathway for the LDLR that is distinct from that used for lipoprotein uptake.
Text
PIIS0022227520375337
- Version of Record
More information
e-pub ahead of print date: 3 June 2013
Published date: August 2013
Keywords:
Caveolae/metabolism, Cells, Cultured, Clathrin/metabolism, Dynamins/metabolism, Endocytosis, HEK293 Cells, HeLa Cells, Hep G2 Cells, Humans, Liver X Receptors, Lysosomes/metabolism, Orphan Nuclear Receptors/metabolism, Receptors, LDL/metabolism, Ubiquitin-Protein Ligases/metabolism
Identifiers
Local EPrints ID: 505331
URI: http://eprints.soton.ac.uk/id/eprint/505331
ISSN: 0022-2275
PURE UUID: b3357376-3632-44d9-b120-1948b1eb8693
Catalogue record
Date deposited: 07 Oct 2025 16:35
Last modified: 08 Oct 2025 02:17
Export record
Altmetrics
Contributors
Author:
Vincenzo Sorrentino
Author:
Jessica K. Nelson
Author:
Elena Maspero
Author:
André R.A. Marques
Author:
Lilith Scheer
Author:
Simona Polo
Author:
Noam Zelcer
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.
View more statistics