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Intracellular trafficking of LRP9 is dependent on two acidic cluster/dileucine motifs

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Abstract

LDL receptor-related protein 9 (LRP9) is a distant member of the low-density lipoprotein receptor (LDLR) superfamily. To date, there are no reports on the cellular distribution of LRP9 or the signals responsible for its localization. Here, we investigated the intracellular localization and trafficking of LRP9. Using confocal microscopy, we demonstrated that LRP9 was not present at the plasma membrane but co-localized with various markers of the trans-Golgi network (TGN) and endosomes. This co-localization was dependent on the presence of two acidic cluster/dileucine (DXXLL) motifs in the cytoplasmic tail of LRP9, which interact with GGA proteins, clathrin adaptors involved in transport between the TGN and endosomes. LRP9 is the first example of a transmembrane protein with an internal GGA-binding sequence in addition to the usual C-terminal motif. An inactivating mutation (LL → AA) in both DXXLL motifs, which completely inhibited the interaction of LRP9 with GGA proteins, led to an intracellular redistribution of LRP9 from the TGN to early endosomes and the cell surface, indicating that the two DXXLL motifs are essential sorting determinants of LRP9. In conclusion, our results suggest that LRP9 cycles between the TGN, endosomes and the plasma membrane through a GGA dependent-trafficking mechanism.

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Acknowledgments

We would like to thank Juan Bonifacino, Richard Leduc and T. Kitamura for DNA constructs and Marilyn Gist Farquhar for the generous gifts of reagents. We would also like to thank Eric Chevet, Catherine Denicourt and Richard Leduc for their constructive comments on the manuscript. This work was supported by grants from the Canadian Institutes for Health Research and a Canada Research Chair to C.L.

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001-12e Avenue Nord, Sherbrooke, QC, Canada, J1H 5N4

    Rémi Boucher, Heidi Larkin, Julie Brodeur, Hugo Gagnon, Caroline Thériault & Christine Lavoie

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  1. Rémi Boucher
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  2. Heidi Larkin
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  3. Julie Brodeur
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Correspondence to Christine Lavoie.

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Boucher, R., Larkin, H., Brodeur, J. et al. Intracellular trafficking of LRP9 is dependent on two acidic cluster/dileucine motifs. Histochem Cell Biol 130, 315–327 (2008). https://doi.org/10.1007/s00418-008-0436-5

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