Publications

Inositol pyrophosphates are high energy signaling molecules involved in cellular processes such as energetic metabolism, telomere maintenance, stress responses, vesicle trafficking, and can mediate protein phosphorylation. While the inositol kinases underlying inositol pyrophosphate biosynthesis and are well characterized, the phosphatases that selectively regulate their cellular pools are not fully described. The DIPP (diphosphoinositol phosphate phosphohydrolase) enzymes of the Nudix protein family have been demonstrated to dephosphorylate inositol pyrophosphates; however, the Saccharomyces cerevisiae homolog Ddp1 prefers inorganic polyphosphate over inositol pyrophosphates. We identified a novel phosphatase of the recently discovered Atypical Dual-Specificity Phosphatase family as a physiologic inositol pyrophosphate phosphatase. Purified recombinant Siw14 hydrolyzes the β-phosphate from 5-diphosphoinositol pentakisphosphate (5PP-IP₅) in vitro. In vivo, siw14Δ yeast mutants possess increased IP₇ levels while heterologous SIW14 overexpression eliminates IP₇ from cells. IP₇ levels increased proportionately when siw14Δ was combined with ddp1Δ or vip1Δ, indicating independent activity by the enzymes encoded by these genes. We conclude that Siw14 is a physiologic phosphatase that modulates inositol pyrophosphates metabolism by dephosphorylating the IP₇ isoform 5PP-IP₅ to IP₆.