期刊
JOURNAL OF LIPID RESEARCH
卷 54, 期 8, 页码 2174-2184出版社
ELSEVIER
DOI: 10.1194/jlr.M037713
关键词
liver X receptor; low density lipoprotein receptor; inducible degrader of low density lipoprotein receptor; E3-ubiquitin ligase; endocytosis; lipoprotein receptors; epsins
资金
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG11627]
- EMBO Young Investigator Program
- Human Frontier Science Program Organization (HFSP)
- VIDI grant from the Netherlands Organization of Scientific Research (NWO)
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.
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