title: ARH directs megalin to the endocytic recycling compartment to regulate its proteolysis and gene expression.
abstract: Receptors internalized by endocytosis can return to the plasma membrane (PM) directly from early endosomes (EE; fast recycling) or they can traffic from EE to the endocytic recycling compartment (ERC) and recycle from there (slow recycling). How receptors are sorted for trafficking along these two pathways remains unclear. Here we show that autosomal recessive hypercholesterolemia (ARH) is required for trafficking of megalin, a member of the LDL receptor family, from EE to the ERC by coupling it to dynein; in the absence of ARH, megalin returns directly to the PM from EE via the connecdenn2/Rab35 fast recycling pathway. Binding of ARH to the endocytic adaptor AP-2 prevents fast recycling of megalin. ARH-mediated trafficking of megalin to the ERC is necessary for γ-secretase mediated cleavage of megalin and release of a tail fragment that mediates transcriptional repression. These results identify a novel mechanism for sorting receptors for trafficking to the ERC and link ERC trafficking to regulated intramembrane proteolysis (RIP) and expression of megalin.
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Mehul
authors.initials: M
authors.lastname: Shah
authors.forename: Oscar Y
authors.initials: OY
authors.lastname: Baterina
authors.forename: Vanessa
authors.initials: V
authors.lastname: Taupin
authors.forename: Marilyn G
authors.initials: MG
authors.lastname: Farquhar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004398:Dyneins / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics / Q000378:metabolism*; D000090204:Mesothelin; D011485:Protein Binding; D021381:Protein Transport; D059748:Proteolysis; D051381:Rats; D050656:Transcription Factor AP-2 / Q000378:metabolism; D014158:Transcription, Genetic; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C501404:Dab2 protein, rat; C469745:LDLRAP1 protein, human; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C000715529:Msln protein, rat; D050656:Transcription Factor AP-2; C575759:Rab35 protein, rat; D004398:Dyneins; D020691:rab GTP-Binding Proteins; D000090204:Mesothelin