title: The LXR-IDOL axis defines a clathrin-, caveolae-, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation.
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.
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center of the University of Amsterdam, 1105AZ Amsterdam, The Netherlands.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Sorrentino
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center of the University of Amsterdam, 1105AZ Amsterdam, The Netherlands.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Nelson
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, 20139 Milan, Italy; and.
authors.forename: Elena
authors.initials: E
authors.lastname: Maspero
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center of the University of Amsterdam, 1105AZ Amsterdam, The Netherlands.
authors.forename: André R A
authors.initials: ARA
authors.lastname: Marques
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center of the University of Amsterdam, 1105AZ Amsterdam, The Netherlands.
authors.forename: Lilith
authors.initials: L
authors.lastname: Scheer
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, 20139 Milan, Italy; and; Dipartimento di Scienze della Salute, Universita' degli Studi di Milano, 20122 Milan, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Polo
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center of the University of Amsterdam, 1105AZ Amsterdam, The Netherlands. Electronic address: n.zelcer@amc.uva.nl.
authors.forename: Noam
authors.initials: N
authors.lastname: Zelcer
mesh_terms: D021941:Caveolae / Q000378:metabolism; D002478:Cells, Cultured; D002966:Clathrin / Q000378:metabolism; D034281:Dynamins / Q000378:metabolism; D004705:Endocytosis; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D000071518:Liver X Receptors; D008247:Lysosomes / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D002966:Clathrin; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011973:Receptors, LDL; C403126:MYLIP protein, human; D044767:Ubiquitin-Protein Ligases; D034281:Dynamins
keywords: E3-ubiquitin ligase; endocytosis; epsins; inducible degrader of low density lipoprotein receptor; lipoprotein receptors; liver X receptor; low density lipoprotein receptor