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Vol. 20, Issue 1, 481-497, January 1, 2009

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Polarized Traffic of LRP1 Involves AP1B and SNX17 Operating on Y-dependent Sorting Motifs in Different Pathways

Maribel Donoso^*, Jorge Cancino^*, Jiyeon Lee, Peter van Kerkhof, Claudio Retamal^*, Guojun Bu, Alfonso Gonzalez^*,, Alfredo Cáceres^||, and María-Paz Marzolo^*

*Centro de Regulación Celular y Patología (CRCP), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile (PUC) and the Millenium Institute for Fundamental and Applied Biology (MIFAB), Santiago, Chile; Departments of Pediatrics, and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110; Department of Cell Biology and Institute of Biomembranes, University Medical Center, Utrech 3584 CX, The Netherlands; Departamento de Inmunología Clínica y Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; and ^||Instituto de Investigación Médica Mercedes y Martín Ferreyra (INIMEC-CONICET), Córdoba, Argentina

Submitted August 6, 2008; Revised October 27, 2008; Accepted October 30, 2008
Monitoring Editor: Jean E. Gruenberg

Low-density lipoprotein receptor–related protein 1 (LRP1) is an endocytic recycling receptor with two cytoplasmic tyrosine-based basolateral sorting signals. Here we show that during biosynthetic trafficking LRP1 uses AP1B adaptor complex to move from a post-TGN recycling endosome (RE) to the basolateral membrane. Then it recycles basolaterally from the basolateral sorting endosome (BSE) involving recognition by sorting nexin 17 (SNX17). In the biosynthetic pathway, Y₂₉ but not N₂₆ from a proximal NPXY directs LRP1 basolateral sorting from the TGN. A N₂₆A mutant revealed that this NPXY motif recognized by SNX17 is required for the receptor's exit from BSE. An endocytic Y₆₃ATL₆₆ motif also functions in basolateral recycling, in concert with an additional endocytic motif (LL_86,87), by preventing LRP1 entry into the transcytotic apical pathway. All this sorting information operates similarly in hippocampal neurons to mediate LRP1 somatodendritic distribution regardless of the absence of AP1B in neurons. LRP1 basolateral distribution results then from spatially and temporally segregation steps mediated by recognition of distinct tyrosine-based motifs. We also demonstrate a novel function of SNX17 in basolateral/somatodendritic recycling from a different compartment than AP1B endosomes.

Address correspondence to: María-Paz Marzolo (mmarzolo{at}bio.puc.cl)