Sorting nexin 17 facilitates LRP recycling in the early endosome.
The low-density lipoprotein (LDL) receptor-related protein (LRP) is a multiligand endocytic receptor and a member of the LDL receptor family. Here we show that sorting nexin 17 (Snx 17) is part of the cellular sorting machinery that regulates cell surface levels of LRP by promoting its recycling. While the phox (PX) domain of Snx 17 interacts with phosphatidylinositol-3-phosphate for membrane association, the FERM domain and the carboxyl-terminal region participate in LRP binding. Immunoelectron microscopy shows that the membrane-bound fraction of Snx 17 is localized to the limiting membrane and recycling tubules of early endosomes. The NPxY motif, proximal to the plasma membrane in the LRP cytoplasmic tail, is identified as the Snx 17-binding motif. Functional mutation of this motif did not interfere with LRP endocytosis, but decreased LRP recycling from endosomes, resulting in increased lysosomal degradation. Similar effects are found after knockdown of endogenous Snx 17 expression by short interfering RNA. We conclude that Snx 17 binds to a motif in the LRP tail distinct from the endocytosis signals and promotes LRP sorting to the recycling pathway in the early endosomes.
van Kerkhof
Peter
P
Department of Pediatrics, Washington University School of Medicine, St Louis, MO 63110, USA.
Lee
Jiyeon
J
McCormick
Lynn
L
Tetrault
Elena
E
Lu
Wenyan
W
Schoenfish
Marissa
M
Oorschot
Viola
V
Strous
Ger J
GJ
Klumperman
Judith
J
Bu
Guojun
G
D020816:Amino Acid Motifs / Q000235:genetics; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D011992:Endosomes / Q000378:metabolism*; D005434:Flow Cytometry; D005453:Fluorescence; D005982:Glutathione Transferase; D006801:Humans; D047468:Immunoprecipitation; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D016253:Microscopy, Immunoelectron; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D058305:Sorting Nexins; D014162:Transfection; D033921:Vesicular Transport Proteins
D002352:Carrier Proteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D034741:RNA, Small Interfering; C487895:SNX17 protein, human; D058305:Sorting Nexins; D033921:Vesicular Transport Proteins; D005982:Glutathione Transferase; D010744:Phosphoric Monoester Hydrolases; C061816:phosphatidylinositol-3-phosphatase