A context dependent requirement for Fig4 catalytic function in yeast

PI lipid phosphatases modulate signaling cascades through localized dephosphorylation of specific phosphoinositides (PI) on subcellular membranes. Additionally, some of these phosphatases regulate cellular processes through lipid phosphatase independent functions. Notably, Fig4, a PI 5‐phosphatase proposed to dephosphorylate PI3,5P2, promotes the synthesis of its substrate independent of its catalytic activity. Fig4 activates its opposing kinase, Fab1, to facilitate dynamic elevation of PI3,5P2 by associating with the Fab1‐Vac14‐Fig4 complex. While Fig4 is critical for development, its catalytic function is not, as catalytically impaired Fig4 rescues neonatal defects in a Fig4 knock‐out mouse. Nevertheless, mice expressing catalytically impaired Fig4 alone display late on‐set neurological abnormalities and reduced life spans indicating that Fig4 catalytic activity is critical for long‐term homeostasis. Strikingly, we show that catalytic impairment of yeast Fig4 is more detrimental to yeast growth on rapamycin and heat stress than total loss of Fig4. Toxicity of catalytically impaired Fig4 can be rescued by co‐expression of wild‐type Fig4 implying that this toxicity results from loss of catalytic function. Moreover, yeast expressing hyperactive Fab1 show similar growth defects on rapamycin and heat stress in the absence of Fig4, which suggests that elevated levels of PI3,5P2 are responsible for this phenotype. These studies provide a new model for investigating the physiological implications of loss of Fig4 catalytic activity. Support or Funding Information NIH R00 GM120511‐04