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.
['Sorrentino|Vincenzo|V|', 'Nelson|Jessica K|JK|', 'Maspero|Elena|E|', 'Marques|André R A|ARA|', 'Scheer|Lilith|L|', 'Polo|Simona|S|', 'Zelcer|Noam|N|']
D021941:Caveolae D002478:Cells, Cultured D002966:Clathrin D034281:Dynamins D004705:Endocytosis D057809:HEK293 Cells D006367:HeLa Cells D056945:Hep G2 Cells D006801:Humans D000071518:Liver X Receptors D008247:Lysosomes D057093:Orphan Nuclear Receptors D011973:Receptors, LDL D044767:Ubiquitin-Protein Ligases
endocytosis liver X receptor E3-ubiquitin ligase epsins inducible degrader of low density lipoprotein receptor lipoprotein receptors low density lipoprotein receptor