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PMID: 16801682 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The phosphoinositide kinase PIKfyve/Fab1p regulates terminal lysosome maturation in Caenorhabditis elegans.

Molecular biology of the cell ·Vol. 17 ·No. 7 ·2006-07-00 ·Pages 3062-74

Nicot AS, Fares H, Payrastre B, Chisholm AD, Labouesse M, Laporte J

Abstract

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.

MeSH Terms
Amino Acid Sequence Animals Caenorhabditis elegans/enzymology,ultrastructure Caenorhabditis elegans Proteins/analysis,genetics,physiology Intracellular Membranes/enzymology,ultrastructure Lysosomes/enzymology,ultrastructure Molecular Sequence Data Mutation Phosphatidylinositol Phosphates/analysis,metabolism Phosphotransferases (Alcohol Group Acceptor)/analysis,genetics,physiology Vacuoles/enzymology,ultrastructure
Chemicals
Caenorhabditis elegans Proteins Phosphatidylinositol Phosphates phosphatidylinositol 3,5-diphosphate PPK-3 protein, C elegans Phosphotransferases (Alcohol Group Acceptor)
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Nicot Anne-Sophie
Department of Molecular Pathology, 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, Illkirch, France.
Fares Hanna
Payrastre Bernard
Chisholm Andrew D
Labouesse Michel
Laporte Jocelyn
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Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1059-1524
DOI
10.1091/mbc.e05-12-1120
Published
2006-07-00
Pages
3062-74
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC1483040
Subset
IM
Grants
NIGMS NIH HHS · R01 GM054657 · United States
NIGMS NIH HHS · R01 GM065235 · United States
NIGMS NIH HHS · GM-54657 · United States
NIGMS NIH HHS · GM-65235 · United States
External Links
PubMed source DOI: 10.1091/mbc.e05-12-1120 PMC Full Text View journal details
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