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First published online September 22, 2005
doi: 10.1242/10.1242/jcs.02568

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Sorting nexin-2 is associated with tubular elements of the early endosome, but is not essential for retromer-mediated endosome-to-TGN transport

Jez G. Carlton^1,*, Miriam V. Bujny^1,*, Brian J. Peter², Viola M. J. Oorschot³, Anna Rutherford¹, Rebecca S. Arkell⁴, Judith Klumperman³, Harvey T. McMahon² and Peter J. Cullen^1,

¹ Henry Wellcome Integrated Signalling Laboratories, Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK
² MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK
³ Cell Microscopy Center, Department of Cell Biology and Institute for Biomembranes, University Medical Centre Utrecht, Utrecht, The Netherlands
⁴ Signalling Programme, The Babraham Institute, Babraham Hall, Cambridge CB2 4AT, UK

Author for correspondence (e-mail: pete.cullen{at}bris.ac.uk)

Accepted 5 July 2005

Sorting nexins are a large family of phox-homology-domain-containing proteins that have been implicated in the control of endosomal sorting. Sorting nexin-1 is a component of the mammalian retromer complex that regulates retrieval of the cation-independent mannose 6-phosphate receptor from endosomes to the trans-Golgi network. In yeast, retromer is composed of Vps5p (the orthologue of sorting nexin-1), Vps17p (a related sorting nexin) and a cargo selective subcomplex composed of Vps26p, Vps29p and Vps35p. With the exception of Vps17p, mammalian orthologues of all yeast retromer components have been identified. For Vps17p, one potential mammalian orthologue is sorting nexin-2. Here we show that, like sorting nexin-1, sorting nexin-2 binds phosphatidylinositol 3-monophosphate and phosphatidylinositol 3,5-bisphosphate, and possesses a Bin/Amphiphysin/Rvs domain that can sense membrane curvature. However, in contrast to sorting nexin-1, sorting nexin-2 could not induce membrane tubulation in vitro or in vivo. Functionally, we show that endogenous sorting nexin-1 and sorting nexin-2 co-localise on high curvature tubular elements of the 3-phosphoinositide-enriched early endosome, and that suppression of sorting nexin-2 does not perturb the degradative sorting of receptors for epidermal growth factor or transferrin, nor the steady-state distribution of the cation-independent mannose 6-phosphate receptor. However, suppression of sorting nexin-2 results in a subtle alteration in the kinetics of cation-independent mannose 6-phosphate receptor retrieval. These data suggest that although sorting nexin-2 may be a component of the retromer complex, its presence is not essential for the regulation of endosome-to-trans Golgi network retrieval of the cation-independent mannose 6-phosphate receptor.

Key words: Sorting nexin, Retromer, CI-MPR, Phosphoinositide, PX-domain

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