How interdiction of inositol pyrophosphate catabolism perturbs the fission yeast response to phosphate starvation.

In fission yeast, inositol-1-pyrophosphates drive the synthesis of vacuolar inorganic polyphosphate (polyP), which serves as a phosphate reservoir during nutrient scarcity. Acute phosphate starvation of wild-type fission yeast cells triggers rapid depletion in tandem of inositol-1-pyrophosphates and polyP, and a gradual transition to G0 quiescence. Here, we report that HASX yeast cells, which lack the three pyrophosphatase enzymes that catabolize inositol pyrophosphates, mount an aberrant response to phosphate starvation associated with sustained elevation of inositol-1-pyrophosphates. This entails immediate cessation of growth; precocious onset of the phosphate starvation transcriptional program; persistently high vacuolar polyP levels; and rapid loss of polysomes, accumulation of 80S monosomes, and inefficient translation of starvation-induced pho1 mRNA. Two key findings are that: (i) the deviant phosphate starvation phenotype in HASX cells is effaced by deletion of vacuolar polyP polymerase Vtc4; and (ii) overdrive of Vtc4-catalyzed polyP synthesis by excess inositol-1-pyrophosphates rapidly exhausts the GTP pool in phosphate-starved HASX cells. GTP depletion, together with precocious repression of genes encoding translation factor GTPases, is the likely cause of the polysome decay. Our results provide new insights into how inositol pyrophosphate signaling and polyP dynamics influence the translation machinery, phosphate homeostasis, and the transcriptional response to nutrient stress.