Homeostatic Influence of Fig4 Outside of the Fab1‐Vac14‐Fig4 Complex in Saccharomyces cerevisiae

TL;DR

A yeast study shows that disease-related mutations in the Fig4 protein can alter how cells respond to a drug, suggesting new ways this protein might influence health.

Contribution

The study reveals a novel role for Fig4 mutants in modulating TORC1 signaling and drug tolerance independently of their usual complex and catalytic activity.

Findings

Fig4 disease-related mutants confer rapamycin tolerance in yeast without binding to the Fab1-Vac14-Fig4 complex.

Rapamycin tolerance conferred by Fig4 mutants is independent of Vac14 and catalytic activity.

Catalytically dead Fig4 that binds the complex increases rapamycin sensitivity.

Abstract

The lipid phosphatase Fig4 is conserved in all eukaryotes and is associated with human neurological diseases for which there are currently no specific therapies. Fig4 functions in both the production and turnover of its lipid substrate, PI3,5P2, through participation in the Fab1‐Vac14‐Fig4 complex with its opposing kinase Fab1. The molecular mechanisms through which Fig4 influences PI3,5P2 production are not fully understood but are believed to require Fig4 binding to the scaffold protein Vac14. We unexpectedly found that multiple Fig4 disease‐related mutants that are impaired in binding to the Fab1‐Vac14‐Fig4 complex dominantly confer tolerance to rapamycin, an inhibitor of the Target of Rapamycin Complex 1 (TORC1), when expressed in
Saccharomyces cerevisiae
. Fig4‐dependent rapamycin tolerance is conferred under moderate heat stress, independent of Vac14 and Fig4 catalytic activity. Conversely, expression of catalytically dead Fig4 that binds stably to the Fab1‐Vac14‐Fig4 complex enhances rapamycin sensitivity. We propose that Fig4 disease‐related mutants alter TORC1 signaling through gain of function under these conditions through an abnormal or sustained interaction with an unknown factor, perhaps by altering PI3,5P2 production. Investigation of the mechanisms whereby Fig4 mutants alter rapamycin tolerance may provide new insights into Fig4 molecular functions with potential relevance for Fig4‐related diseases.

Disease‐related Fig4 mutants displaying impaired association with the Fab1‐Vac14‐Fig4 complex confer rapamycin tolerance in
Saccharomyces cerevisiae
independent of Vac14 and Fig4 catalytic function. Fig4 may thus modulate homeostasis through uncharacterized molecular interactions that lead to altered function when not bound to Vac14.

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