Reeves HE, King A, Khan I, Thomas A, Chung C, Sivaprakash A, Hall HA, McGuire C, Cruz V, Habib A, Dotson L, Lee SR, Darbro CL, Strunk BS

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 ...

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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.

Date: Jul. 31, 2025

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