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 gene inducible degrader of the LDLR (IDOL), an E3-ubiquitin ligase that promotes ubiquitylation and lysosomal degradation of the LDLR.How Leisure al90d230k 90cm Electric Range Cooker Induction Top 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 Standing Shelves pathway for the LDLR that is distinct from that used for lipoprotein uptake.