IDOL stimulates clathrin-independent endocytosis and multivesicular body-mediated lysosomal degradation of the low-density lipoprotein receptor.
The low-density lipoprotein receptor (LDLR) is a critical determinant of plasma cholesterol levels that internalizes lipoprotein cargo via clathrin-mediated endocytosis. Here, we show that the E3 ubiquitin ligase IDOL stimulates a previously unrecognized, clathrin-independent pathway for LDLR internalization. Real-time single-particle tracking and electron microscopy reveal that IDOL is recruited to ... the plasma membrane by LDLR, promotes LDLR internalization in the absence of clathrin or caveolae, and facilitates LDLR degradation by shuttling it into the multivesicular body (MVB) protein-sorting pathway. The IDOL-dependent degradation pathway is distinct from that mediated by PCSK9 as only IDOL employs ESCRT (endosomal-sorting complex required for transport) complexes to recognize and traffic LDLR to lysosomes. Small interfering RNA (siRNA)-mediated knockdown of ESCRT-0 (HGS) or ESCRT-I (TSG101) components prevents IDOL-mediated LDLR degradation. We further show that USP8 acts downstream of IDOL to deubiquitinate LDLR and that USP8 is required for LDLR entry into the MVB pathway. These results provide key mechanistic insights into an evolutionarily conserved pathway for the control of lipoprotein receptor expression and cellular lipid uptake.
Mesh Terms:
Animals, Cell Cycle Proteins, Cell Line, Clathrin, DNA-Binding Proteins, Endocytosis, Endopeptidases, Endosomal Sorting Complexes Required for Transport, Guanine Nucleotide Exchange Factors, HEK293 Cells, HeLa Cells, Hep G2 Cells, Humans, Lipoproteins, LDL, Lysosomes, Mice, Multivesicular Bodies, Nuclear Proteins, Phosphoproteins, Proprotein Convertases, Protein Transport, RNA Interference, RNA, Small Interfering, Receptors, LDL, Serine Endopeptidases, Transcription Factors, Ubiquitin Thiolesterase, Ubiquitin-Protein Ligases, Ubiquitination
Animals, Cell Cycle Proteins, Cell Line, Clathrin, DNA-Binding Proteins, Endocytosis, Endopeptidases, Endosomal Sorting Complexes Required for Transport, Guanine Nucleotide Exchange Factors, HEK293 Cells, HeLa Cells, Hep G2 Cells, Humans, Lipoproteins, LDL, Lysosomes, Mice, Multivesicular Bodies, Nuclear Proteins, Phosphoproteins, Proprotein Convertases, Protein Transport, RNA Interference, RNA, Small Interfering, Receptors, LDL, Serine Endopeptidases, Transcription Factors, Ubiquitin Thiolesterase, Ubiquitin-Protein Ligases, Ubiquitination
Mol. Cell. Biol.
Date: Apr. 01, 2013
PubMed ID: 23382078
View in: Pubmed Google Scholar
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