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  • The EMBO Journal (2008) 27, 3221 - 3234
  • doi:10.1038/emboj.2008.248

Published online: 27 November 2008

VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P2 in yeast and mouseEMBO Open

Natsuko Jin1,a, Clement Y Chow2,a, Li Liu3, Sergey N Zolov1, Roderick Bronson4, Muriel Davisson5, Jason L Petersen1, Yanling Zhang1, Sujin Park1, Jason E Duex1, Daniel Goldowitz6, Miriam H Meisler2 and Lois S Weisman1

  1. Department of Cell and Developmental Biology and Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
  2. Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
  3. Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA
  4. Department of Pathology, Harvard Medical School, Boston, MA, USA
  5. Mutant Resources Program, The Jackson Laboratory, Bar Harbor, ME, USA
  6. Department of Medical Genetics, University of British Columbia, Vancouver, BC, USA

Correspondence to:

Lois S Weisman, Life Sciences Institute, 210 Washtenaw Avenue, Room 6437, The University of Michigan, Ann Arbor, MI 48109-2216, USA. Tel.: +734 647 2539; Fax: +734 615 5499; E-mail: lweisman@umich.edu

Miriam H Meisler, Life Sciences Institute, 210 Washtenaw Avenue, Room 6437, The University of Michigan, Ann Arbor, MI 48109-2216, USA. Tel.: +734 647 2539; Fax: +734 615 5499; E-mail: meislerm@umich.edu

aThese authors contributed equally to this work

Received 28 August 2008; Accepted 23 October 2008

The signalling lipid PI(3,5)P2 is generated on endosomes and regulates retrograde traffic to the trans-Golgi network. Physiological signals regulate rapid, transient changes in PI(3,5)P2 levels. Mutations that lower PI(3,5)P2 cause neurodegeneration in human patients and mice. The function of Vac14 in the regulation of PI(3,5)P2 was uncharacterized previously. Here, we predict that yeast and mammalian Vac14 are composed entirely of HEAT repeats and demonstrate that Vac14 exerts an effect as a scaffold for the PI(3,5)P2 regulatory complex by direct contact with the known regulators of PI(3,5)P2: Fig4, Fab1, Vac7 and Atg18. We also report that the mouse mutant ingls (infantile gliosis) results from a missense mutation in Vac14 that prevents the association of Vac14 with Fab1, generating a partial complex. Analysis of ingls and two additional mutants provides insight into the organization of the PI(3,5)P2 regulatory complex and indicates that Vac14 mediates three distinct mechanisms for the rapid interconversion of PI3P and PI(3,5)P2. Moreover, these studies show that the association of Fab1 with the complex is essential for viability in the mouse.

  • Keywords:

    • pale tremor,
    • phosphatidylinositol 3,5-bisphosphate,
    • PIKfyve,
    • Saccharomyces cerevisiae

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The EMBO Journal is published by Nature Publishing Group on behalf of European Molecular Biology Organization