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Vol. 18, Issue 11, 4232-4244, November 2007

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Atg18 Regulates Organelle Morphology and Fab1 Kinase Activity Independent of Its Membrane Recruitment by Phosphatidylinositol 3,5-Bisphosphate

Jem A. Efe^*, Roberto J. Botelho^,, and Scott D. Emr^,,

*Division of Biology, Department of Cellular and Molecular Medicine, and The Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093-0668; and Cornell Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853

Submitted April 4, 2007; Revised July 20, 2007; Accepted August 8, 2007
Monitoring Editor: John York

The lipid kinase Fab1 governs yeast vacuole homeostasis by generating PtdIns(3,5)P₂ on the vacuolar membrane. Recruitment of effector proteins by the phospholipid ensures precise regulation of vacuole morphology and function. Cells lacking the effector Atg18p have enlarged vacuoles and high PtdIns(3,5)P₂ levels. Although Atg18 colocalizes with Fab1p, it likely does not directly interact with Fab1p, as deletion of either kinase activator—VAC7 or VAC14—is epistatic to atg18: atg18vac7 cells have no detectable PtdIns(3,5)P₂. Moreover, a 2xAtg18 (tandem fusion) construct localizes to the vacuole membrane in the absence of PtdIns(3,5)P₂, but requires Vac7p for recruitment. Like the endosomal PtdIns(3)P effector EEA1, Atg18 membrane binding may require a protein component. When the lipid requirement is bypassed by fusing Atg18 to ALP, a vacuolar transmembrane protein, vac14 vacuoles regain normal morphology. Rescue is independent of PtdIns(3,5)P₂, as mutation of the phospholipid-binding site in Atg18 does not prevent vacuole fission and properly regulates Fab1p activity. Finally, the vacuole-specific type-V myosin adapter Vac17p interacts with Atg18p, perhaps mediating cytoskeletal attachment during retrograde transport. Atg18p is likely a PtdIns(3,5)P₂"sensor," acting as an effector to remodel membranes as well as regulating its synthesis via feedback that might involve Vac7p.

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

Address correspondence to: Scott D. Emr (sde26{at}cornell.edu).

Abbreviations used: PtdIns, phosphatidylinositol; ALP, alkaline phosphatase; Cvt, cytoplasm-to-vacuole transport.

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