VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse.
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.
Jin
Natsuko
N
Department of Cell and Developmental Biology and Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109-2216, USA.
Chow
Clement Y
CY
Liu
Li
L
Zolov
Sergey N
SN
Bronson
Roderick
R
Davisson
Muriel
M
Petersen
Jason L
JL
Zhang
Yanling
Y
Park
Sujin
S
Duex
Jason E
JE
Goldowitz
Daniel
D
Meisler
Miriam H
MH
Weisman
Lois S
LS
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000071183:Autophagy-Related Proteins; D005328:Fetal Viability; D005420:Flavoproteins / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008954:Models, Biological; D020125:Mutation, Missense; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D020449:Repetitive Sequences, Amino Acid; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D020798:Two-Hybrid System Techniques
C441008:ATG18 protein, S cerevisiae; D000071183:Autophagy-Related Proteins; D005420:Flavoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; D029701:Saccharomyces cerevisiae Proteins; C494631:VAC14 protein, human; C452436:VAC7 protein, S cerevisiae; C525133:Vac14 protein, mouse; C106336:phosphatidylinositol 3,5-diphosphate; C483312:phosphoinositide 3-phosphate; C095504:FAB1 protein, S cerevisiae; D017853:Phosphotransferases (Alcohol Group Acceptor); C110669:FIG4 protein, S cerevisiae; D010744:Phosphoric Monoester Hydrolases