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

Blog Article

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 Jeans 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 opheliasmuse.com 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.