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SNX4 coordinates endosomal sorting of TfnR with dynein-mediated transport into the endocytic recycling compartment

Abstract

SNX-BAR proteins are a sub-family of sorting nexins implicated in endosomal sorting. Here, we establish that through its phox homology (PX) and Bin–Amphiphysin–Rvs (BAR) domains, sorting nexin-4 (SNX4) is associated with tubular and vesicular elements of a compartment that overlaps with peripheral early endosomes and the juxtanuclear endocytic recycling compartment (ERC). Suppression of SNX4 perturbs transport between these compartments and causes lysosomal degradation of the transferrin receptor (TfnR). Through an interaction with KIBRA, a protein previously shown to bind dynein light chain 1, we establish that SNX4 associates with the minus end-directed microtubule motor dynein. Although suppression of KIBRA and dynein perturbs early endosome-to-ERC transport, TfnR sorting is maintained. We propose that by driving membrane tubulation, SNX4 coordinates iterative, geometric-based sorting of the TfnR with the long-range transport of carriers from early endosomes to the ERC. Finally, these data suggest that by associating with molecular motors, SNX-BAR proteins may coordinate sorting with carrier transport between donor and recipient membranes.

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Figure 1: SNX4 is associated with an endosomal compartment that overlaps with elements of the peripheral early endosome and the juxtanuclear ERC.
Figure 2: SNX4 associates with a highly dynamic tubular-vesicular endosomal compartment in which receptor sorting occurs.
Figure 3: siRNA-mediated knockdown of SNX4 decreases the level of TfnR through mis-sorting of the receptor into the lysosomal degradative pathway.
Figure 4: Suppression of SNX4 causes the dispersal of early endosomes and the juxtanuclear recycling compartment to the cell periphery.
Figure 5: SNX4 interacts with the dynein interactor KIBRA.
Figure 6: Suppression of SNX4 or KIBRA perturbs the transport of Tfn to the ERC.
Figure 7: Suppression of dynein perturbs transport of TfnR to the ERC.
Figure 8: A schematic representation of a model for the role of SNX4 in endosomal sorting and transport of the TfnR.

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Acknowledgements

This work was funded by the Wellcome Trust and a Medical Research Council Infrastructure Award (G4500006), which established the School of Medical Sciences Cell Imaging Facility. A.C.R was the recipient of a Medical Research Council Studentships. We thank M. Jepson and A. Leard for their assistance, J. Lane and M. McCaffrey for helpful discussion, and V. Hsu for ACAP1 constructs. D.J.S. is supported by the Medical Research Council through a Senior Research Fellowship.

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C.J.T., A.C.R., K.J.P., T.W., J.O., N.A. and J.G.C. contributed to experimental work, project planning, data analysis and manuscript writing. J.K. provided vital reagents and antibodies. D.J.S. and P.J.C. contributed to experimental work, project planning and manuscript writing.

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Correspondence to Peter J. Cullen.

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Traer, C., Rutherford, A., Palmer, K. et al. SNX4 coordinates endosomal sorting of TfnR with dynein-mediated transport into the endocytic recycling compartment. Nat Cell Biol 9, 1370–1380 (2007). https://doi.org/10.1038/ncb1656

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