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

• Natsuko Jin ^[1] ; Clement Y Chow ^[1] ; Li Liu ^[2] ; Sergey N Zolov ^[1] ; Roderick Bronson ^[3] ; Muriel Davisson ^[5] ; Jason L Petersen ^[1] ; Yanling Zhang ; Sujin Park ^[1] ; Jason E Duex ^[1] ; Daniel Goldowitz ^[4] ; Miriam H Meisler ^[1] ; Lois S Weisman ^[1]
  1. [1] University of Michigan–Ann Arbor

     University of Michigan–Ann Arbor

     City of Ann Arbor, Estados Unidos

     
  2. [2] University of Tennessee Health Science Center

     University of Tennessee Health Science Center

     Estados Unidos

     
  3. [3] Harvard Medical School

     Harvard Medical School

     City of Boston, Estados Unidos

     
  4. [4] Department of Medical Genetics, University of British Columbia, Vancouver, BC, USA
  5. [5] Mutant Resources Program, The Jackson Laboratory, Bar Harbor, ME, USA

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 27, Nº. 24, 2008, págs. 3221-3234
• Idioma: inglés
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  • 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.