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AP-4 binds basolateral signals and participates in basolateral sorting in epithelial MDCK cells

Nature Cell Biology volume 4, pages 154–159 (2002)Cite this article

Abstract

Adaptors are heterotetrameric complexes that mediate the incorporation of cargo into transport vesicles by interacting with sorting signals present in the cytosolic domain of transmembrane proteins. Four adaptors, AP-1 (β1, γ, μ1A or μ1B, σ1), AP-2 (β2, α, μ2, σ2), AP-3 (β3, δ, μ3, σ3) or AP-4 (β4, ɛ, μ4, σ4), have been characterized1,2. AP-1 and AP-3 mediate sorting events at the level of the TGN and/or endosomes, whereas AP-2 functions in endocytic clathrin coated vesicle formation; no function is known so far for AP-4. Here, we show that AP-4 can bind different types of cytosolic signals known to mediate basolateral transport in epithelial cells. Furthermore, in MDCK cells with depleted μ4 protein levels, several basolateral proteins are mis-sorted to the apical surface, showing that AP-4 participates in basolateral sorting in epithelial cells.

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Figure 1: Characterization of AP-4 in MDCK cells.
Figure 2: Partial localization of AP-4 with AP-1, furin, MPR46 and internalized BSA–gold, but not with lysobisphosphatidic acid.
Figure 3: Binding of AP-4 to the FI-based basolateral-sorting motif in furin (a), the tyrosine-based, membrane distal basolateral sorting signal in the LDLR (b), the unconventional basolateral sorting determinant in the MPR46 (c) and in the TfR (d).
Figure 4: Characterization of μ4-depleted MDCK cells and basolateral sorting in cells with reduced AP-4 levels.

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Acknowledgements

We thank M. Robinson, P. Schu, J. Gruenberg, G. Thomas and G. Ojakian for antibodies, as well as K. von Figura and R. Sitia for stimulating discussions and their generous support. We apologize to our colleagues whose work could not be cited owing to space limitations. This work was supported by grants from the Swiss and German Science Foundations to W.H. (31-31978.91 and 31-50581.97) and S.H. (SFB523) respectively, and by the Biomedical Research Council of Singapore to W.H., as well as fellowships from the Telethon Foundation to T.S. (380bs) and the Leenaards Foundation to W.H. W.H. is an adjunct staff member at the Department of Physiology, National University of Singapore.

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Author notes

  1. Thomas Simmen

    Present address: Vollum Institute, OHSU, Portland, OR 97201, USA

  2. Thomas Simmen and Stefan Höning: These authors contributed equally to the work.

Authors and Affiliations

  1. Institute of Biochemistry, University of Lausanne, Epalinges, CH-1066, Switzerland

    Thomas Simmen & Walter Hunziker

  2. Biochemistry II, University of Göttingen, Göttingen, 37073, Germany

    Stefan Höning

  3. Institute for Cell Biology, University of Bonn, Bonn, 53122, Germany

    Ann Icking & Ritva Tikkanen

  4. Institute of Molecular and Cell Biology, 30 Medical Drive, 117609, Singapore

    Walter Hunziker

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Correspondence to Walter Hunziker.

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Simmen, T., Höning, S., Icking, A. et al. AP-4 binds basolateral signals and participates in basolateral sorting in epithelial MDCK cells. Nat Cell Biol 4, 154–159 (2002). https://doi.org/10.1038/ncb745

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