Fig4 confers tolerance to rapamycin in a Ste20-dependent manner independent of the Vac14 scaffold

Summary StatementDisease-related Fig4 mutants displaying impaired association with the Fab1-Vac14-Fig4 complex confer tolerance to rapamycin in Saccharomyces cerevisiae independent of Vac14 in a Ste20-dependent manner. Fig4 can thus modulate homeostasis through association with pathways outside of the Fab1-Vac14-Fig4 complex in yeast. The lipid phosphatase Fig4 modulates the production and turnover of the signaling lipid PI3,5P2 through participation in a complex with its opposing kinase, Fab1, and the scaffold protein Vac14. Fig4 point mutations are associated with neurological diseases for which there are currently no specific therapies. Pathology involving Fig4 is generally attributed to disruption of the Fab1-Vac14-Fig4 complex. Through genetic manipulations in yeast we show that expression of Fig4 disease-related mutants confers tolerance to rapamycin, an inhibitor of the master growth activator TORC1. This phenotype is dominantly conferred at high temperatures by Fig4 mutants that bind poorly to Vac14 or by excess wild-type Fig4. Rapamycin tolerance does not require Fig4 catalytic activity or Vac14, suggesting that Fig4 mediates this altered stress response through context-inappropriate binding interactions with unknown proteins. The p21-activated kinase Ste20 is specifically required for this novel Vac14-independent Fig4 function. Our study shows that Fig4 can modulate homeostasis in Saccharomyces cerevisiae through interactions outside the Fab1-Vac14-Fig4 complex.