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A selective PIKfyve inhibitor blocks PtdIns(3,5)P 2 production and disrupts endomembrane transport and retroviral budding
Author(s) -
Jefferies Harold B J,
Cooke Frank T,
Jat Parmjit,
Boucheron Christine,
Koizumi Tomonobu,
Hayakawa Masahiko,
Kaizawa Hiroyuki,
Ohishi Takahide,
Workman Paul,
Waterfield Michael D,
Parker Peter J
Publication year - 2008
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/sj.embor.7401155
Subject(s) - endosome , microbiology and biotechnology , endomembrane system , phosphatidylinositol , biology , compartment (ship) , kinase , intracellular , endoplasmic reticulum , golgi apparatus , oceanography , geology
Phosphoinositides have crucial roles in cellular controls, many of which have been established through the use of small‐molecule inhibitors. Here, we describe YM201636, a potent inhibitor of the mammalian class III phosphatidylinositol phosphate kinase PIKfyve, which synthesizes phosphatidylinositol 3,5‐bisphosphate. Acute treatment of cells with YM201636 shows that the PIKfyve pathway is involved in the sorting of endosomal transport, with inhibition leading to the accumulation of a late endosomal compartment and blockade of retroviral exit. Inhibitor specificity is shown by the use of short interfering RNA against the target, as well as by rescue with the drug‐resistant yeast orthologue Fab1. We concluded that the phosphatidylinositol 3,5‐bisphosphate pathway is integral to endosome formation, determining morphology and cargo flux.