Secreted acid phosphatases maintain replicative lifespan via inositol polyphosphate metabolism in budding yeast

Abstract

Secreted acid phosphatases (APases) dephosphorylate extracellular organic phosphate compounds to supply inorganic phosphate (Pi) to maintain cellular functions. Here, we show that APases are necessary to maintain a normal replicative lifespan in Saccharomyces cerevisiae. Deletion of all four APase genes shortened the lifespan in yeast strains on synthetic media (irrespective of the concentrations of Pi in the media), but it did not affect the intracellular ortho‐ and polyphosphate levels. Deletion of inositol‐pentakisphosphate 2‐kinase (IPK1), which encodes inositol‐pentakisphosphate 2‐kinase, restored the lifespan in APase‐null mutants, and IPK1 overexpression shortened the lifespan in wild‐type strains. Overexpression of inositol hexakisphosphate (IP6) and heptakisphosphate kinases, KCS1 and VIP1, recovered the lifespan in APase‐null mutants. Thus, yeast APases modulate the replicative lifespan, probably through dephosphorylation of intracellular IP6.

Kcs1 and Vip1: The Key Enzymes behind Inositol Pyrophosphate Signaling in Saccharomyces cerevisiae

“…Phosphate is an important determinant for lifespan regulation in many organisms. In yeast, it was shown that high levels of intracellular IP 6 reduce the lifespan [53]: research on knockout mutants of different secreted acid phosphatases (APases such as PHO3, PHO5, PHO11, PHO12) demonstrated a shorter lifespan, regardless of the levels of external phosphate compounds; to uncover the substrates through which APases exert their lifespanregulatory effects, the study conducted a screening involving the disruption of enzymes in the polyphosphate pathway. The results revealed a connection between a shorter lifespan and higher IP 6 levels.…”