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Vol. 17, Issue 7, 3062-3074, July 2006

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The Phosphoinositide Kinase PIKfyve/Fab1p Regulates Terminal Lysosome Maturation in Caenorhabditis elegans

Anne-Sophie Nicot^*, Hanna Fares, Bernard Payrastre, Andrew D. Chisholm, Michel Labouesse^||, and Jocelyn Laporte^*

Departments of *Molecular Pathology and ^||Developmental Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U596, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7104, Université Louis Pasteur de Strasbourg, Collège de France, 67404 Illkirch, France; Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721; Oncogenesis and Signaling in Hematopoietic Cells, Institut National de la Santé et de la Recherche Médicale U563, Centre de Physiopathologie de Toulouse Purpan, Institut Fédératif de Recherche 30, Hôpital Purpan, 31059 Toulouse, France; and Department of Molecular, Cell, and Development Biology, Sinsheimer Laboratories, University of California, Santa Cruz, CA 95064

Submitted December 13, 2005; Revised April 13, 2006; Accepted April 18, 2006
Monitoring Editor: Jean Gruenberg

Membrane dynamics is necessary for cell homeostasis and signal transduction and is in part regulated by phosphoinositides. Pikfyve/Fab1p is a phosphoinositide kinase that phosphorylates phosphatidylinositol 3-monophosphate into phosphatidylinositol-3,5-bisphosphate [PtdIns(3,5)P₂] and is implicated in membrane homeostasis in yeast and in mammalian cells. These two phosphoinositides are substrates of myotubularin phosphatases found mutated in neuromuscular diseases. We studied the roles of phosphatidylinositol phosphate kinase 3 (PPK-3), the orthologue of PIKfyve/Fab1p, in a multicellular organism, Caenorhabditis elegans. Complete loss of ppk-3 function induces developmental defects characterized by embryonic lethality, whereas partial loss of function leads to growth retardation. At the cellular level, ppk-3 mutants display a striking enlargement of vacuoles positive for lysosome-associated membrane protein 1 in different tissues. In the intestine, RAB-7–positive late endosomes are also enlarged. Membranes of the enlarged lysosomes originate at least in part from smaller lysosomes, and functional and genetic analyses show that the terminal maturation of lysosomes is defective. Protein degradation is not affected in the hypomorphic ppk-3 mutant and is thus uncoupled from membrane retrieval. We measured the level of PtdIns(3,5)P₂ and showed that its production is impaired in this mutant. This work strongly suggests that the main function of PPK-3 is to mediate membrane retrieval from matured lysosomes through regulation of PtdIns(3,5)P₂.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Jocelyn Laporte ( mtm{at}igbmc.u-strasbg.fr)

Abbreviations used: CUP, coelomocyte uptake defective; LGG-1, LC3, GABARAP, and GATE-16; MVB, multivesicular body; PIKfyve, phosphatidylinositol kinase Fab1p, YoTb, Vac1p, EEA1, Fab1p: formation of aploid and binucleate cells; LMP, lysosome-associated membrane protein; PPK-3, phosphatidylinositol phosphate kinase 3; PtdIns(3)P, phosphatidylinositol-3-monophosphate; PtdIns(3,5)P₂, phosphatidylinositol-3,5-bisphosphate; RME, receptor-mediated endocytosis.

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