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PMID: 19037259 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse.

The EMBO journal ·Vol. 27 ·No. 24 ·2008-12-17 ·Pages 3221-34

Jin N, Chow CY, Liu L, Zolov SN, Bronson R, Davisson M, Petersen JL, Zhang Y, Park S, Duex JE, Goldowitz D, Meisler MH, Weisman LS

Abstract

The signalling lipid PI(3,5)P(2) is generated on endosomes and regulates retrograde traffic to the trans-Golgi network. Physiological signals regulate rapid, transient changes in PI(3,5)P(2) levels. Mutations that lower PI(3,5)P(2) cause neurodegeneration in human patients and mice. The function of Vac14 in the regulation of PI(3,5)P(2) 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)P(2) regulatory complex by direct contact with the known regulators of PI(3,5)P(2): 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)P(2) regulatory complex and indicates that Vac14 mediates three distinct mechanisms for the rapid interconversion of PI3P and PI(3,5)P(2). Moreover, these studies show that the association of Fab1 with the complex is essential for viability in the mouse.

MeSH Terms
Amino Acid Substitution/genetics Animals Autophagy-Related Proteins Fetal Viability Flavoproteins/metabolism Humans Intracellular Signaling Peptides and Proteins/chemistry,genetics,metabolism Membrane Proteins/chemistry,genetics,metabolism Mice/metabolism Mice, Inbred C57BL Mice, Inbred DBA Mice, Knockout Models, Biological Mutation, Missense Phosphatidylinositol Phosphates/metabolism Phosphatidylinositols/metabolism Phosphoric Monoester Hydrolases Phosphotransferases (Alcohol Group Acceptor)/metabolism Protein Binding Protein Interaction Domains and Motifs Protein Structure, Secondary Repetitive Sequences, Amino Acid Saccharomyces cerevisiae/metabolism Saccharomyces cerevisiae Proteins/metabolism Two-Hybrid System Techniques
Chemicals
ATG18 protein, S cerevisiae Autophagy-Related Proteins Flavoproteins Intracellular Signaling Peptides and Proteins Membrane Proteins Phosphatidylinositol Phosphates Phosphatidylinositols Saccharomyces cerevisiae Proteins VAC14 protein, human VAC7 protein, S cerevisiae Vac14 protein, mouse phosphatidylinositol 3,5-diphosphate phosphoinositide 3-phosphate FAB1 protein, S cerevisiae Phosphotransferases (Alcohol Group Acceptor) FIG4 protein, S cerevisiae Phosphoric Monoester Hydrolases
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Jin Natsuko
Department of Cell and Developmental Biology and Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109-2216, USA.
Chow Clement Y
Liu Li
Zolov Sergey N
Bronson Roderick
Davisson Muriel
Petersen Jason L
Zhang Yanling
Park Sujin
Duex Jason E
Goldowitz Daniel
Meisler Miriam H
Weisman Lois S
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32 references, click to expand
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.1038/emboj.2008.248
Published
2008-12-17
Epub
2008-00-27
Pages
3221-34
Language
English
Region
England
NLM ID
8208664
PMCID
PMC2600653
Subset
IM
Grants
NCRR NIH HHS · RR01183 · United States
NIGMS NIH HHS · T32 GM07544 · United States
NINDS NIH HHS · R01 NS064015 · United States
NIGMS NIH HHS · R01-GM24872 · United States
NIGMS NIH HHS · R01 GM024872 · United States
NIGMS NIH HHS · T32 GM007544 · United States
NIGMS NIH HHS · R01 GM050403 · United States
NIGMS NIH HHS · R01-GM50403 · United States
Corrections
CommentIn
PMID: 19158662
External Links
PubMed source DOI: 10.1038/emboj.2008.248 PMC Full Text View journal details
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