A Selective PIKfyve Inhibitor Blocks PtdIns(3,5)P(2) Production and Disrupts Endomembrane Transport and Retroviral Budding

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2008 Jan 12

PMID 18188180

Citations 153

Authors

Harold B J Jefferies

Frank T Cooke

Parmjit Jat

Christine Boucheron

Tomonobu Koizumi

Masahiko Hayakawa

Hiroyuki Kaizawa

Takahide Ohishi

Paul Workman

Michael D Waterfield

Peter J Parker

Affiliations

Soon will be listed here.

Abstract

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.

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