Cellular adaptations of fission yeast to inositol starvation

ABSTRACT Inositol is an essential nutrient and a precursor of phosphorylated metabolites that play important roles in cell physiology. Here we characterize the impact of intracellular inositol deficiency, taking advantage of fission yeast Schizosaccharomyces pombe , an obligate inositol auxotroph, as a model system. We find that cells deprived of inositol ceased growth after two or three rounds of division, with genome content indicative of a G2 arrest. Inositol starvation elicited (i) widespread changes in the expression of genes involved in lipid metabolism and inositol polyphosphate dynamics, associated with an across-the-board elevation of triacylglycerol lipids; (ii) depletion of glycerophosphoinositol and accumulation of glycerophosphocholine and choline; (iii) selective depletion of inositol pyrophosphate 1,5-IP 8 , and depletion of polyphosphate; (iv) upregulation of autophagy genes; (v) downregulation of genes for the biogenesis and function of ribosomes and tRNAs, accompanied by conversion of polysomes to 80S monosomes; and (vi) large-magnitude changes in mRNAs encoding transcription factors. Our study underscores distinctive and shared features of the cellular responses to inositol deficiency versus phosphate deficiency that enhance our understanding of nutrient stress. IMPORTANCE Inositol is an essential precursor of diverse phosphorylated derivatives that govern cell signaling, glucose and lipid metabolism, and cellular phosphate homeostasis. To probe how cells adapt to inositol deprivation, we exploited the fission yeast Schizosaccharomyces pombe , which is unable to synthesize inositol and requires exogenous inositol for growth. Via genome-wide analysis of changes in mRNA levels and tracking the status of inositol-adjacent metabolites, we highlight adaptive responses specific to inositol starvation that affect lipid metabolism and inositol pyrophosphate signaling. Clues to the origins of the transcriptome remodeling during inositol starvation emerged from the large-magnitude increases in mRNAs encoding certain RNA polymerase II transcription factors, which correlated with increased expression of their putative client genes.