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First published online 5 September 2006
doi: 10.1242/jcs.03153

Journal of Cell Science 119, 3944-3957 (2006)
Published by The Company of Biologists 2006
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Research Article

The mammalian phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) regulates endosome-to-TGN retrograde transport

Anna C. Rutherford1, Colin Traer1, Thomas Wassmer1, Krupa Pattni2, Miriam V. Bujny1, Jeremy G. Carlton1,*, Harald Stenmark2 and Peter J. Cullen1,{ddagger}

1 The Henry Wellcome Integrated Signalling Laboratories, Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol, BS8 1TD, UK
2 Department of Biochemistry, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway

{ddagger} Author for correspondence (e-mail: Pete.Cullen{at}bris.ac.uk)

Accepted 27 June 2006

The yeast gene fab1 and its mammalian orthologue Pip5k3 encode the phosphatidylinositol 3-phosphate [PtdIns(3)P] 5-kinases Fab1p and PIKfyve, respectively, enzymes that generates phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P2]. A shared feature of fab1{Delta} yeast cells and mammalian cells overexpressing a kinase-dead PIKfyve mutant is the formation of a swollen vacuolar phenotype: a phenotype that is suggestive of a conserved function for these enzymes and their product, PtdIns(3,5)P2, in the regulation of endomembrane homeostasis. In the current study, fixed and live cell imaging has established that, when overexpressed at low levels in HeLa cells, PIKfyve is predominantly associated with dynamic tubular and vesicular elements of the early endosomal compartment. Moreover, through the use of small interfering RNA, it has been shown that suppression of PIKfyve induces the formation of swollen endosomal structures that maintain their early and late endosomal identity. Although internalisation, recycling and degradative sorting of receptors for epidermal growth factor and transferrin was unperturbed in PIKfyve suppressed cells, a clear defect in endosome to trans-Golgi-network (TGN) retrograde traffic was observed. These data argue that PIKfyve is predominantly associated with the early endosome, from where it regulates retrograde membrane trafficking to the TGN. It follows that the swollen endosomal phenotype observed in PIKfyve-suppressed cells results primarily from a reduction in retrograde membrane fission rather than a defect in multivesicular body biogenesis.

Key words: PIKfyve, Fab1p, Early endosome, Phosphatidylinositol (3,5)-bisphosphate, Endosomal sorting


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© The Company of Biologists Ltd 2006