Tandem inactivation of inositol pyrophosphatases Asp1, Siw14, and Aps1 illuminates functional redundancies in inositol pyrophosphate catabolism in fission yeast Journal Article
| Authors: | Schwer, B.; Prucker, I.; Sanchez, A. M.; Babor, J.; Jessen, H. J.; Shuman, S. |
| Article Title: | Tandem inactivation of inositol pyrophosphatases Asp1, Siw14, and Aps1 illuminates functional redundancies in inositol pyrophosphate catabolism in fission yeast |
| Abstract: | Inositol pyrophosphates 5-IP7, 1-IP7, and 1,5-IP8 are eukaryal signaling molecules that influence cell physiology, especially phosphate homeostasis. In fission yeast, 1,5-IP8 and 1-IP7 impact gene expression by acting as agonists of RNA 3'-process-ing and transcription termination. 1,5-IP8 is synthesized by position-specific kinases Kcs1 and Asp1 that convert IP6 to 5-IP7 and 5-IP7 to 1,5-IP8, respectively. Inositol pyrophosphatase enzymes Asp1 (a histidine acid phosphatase), Siw14 (a cysteinyl phosphatase), and Aps1 (a Nudix hydrolase) are agents of inositol pyrophosphate catabolism in fission yeast. Whereas Asp1, Siw14, and Aps1 are individually inessential, double pyrophosphatase mutants asp1-H397A aps1∆ and siw14∆ aps1∆ display severe growth defects caused by overzealous 3'-processing/termination. By applying CE-ESI-MS to profile the inositol pyrophosphate content of fission yeast mutants in which inositol pyrophosphate toxicity is genetically suppressed, we elucidated the functional redundancies of the Asp1, Siw14, and Aps1 pyrophosphatases. Asp1, which exclusively cleaves the 1-β-phosphate, and Aps1, which prefers to cleave the 1-β-phosphate, play essential overlapping roles in guarding against the accumulation of toxic levels of 1-IP7. Aps1 and Siw14 together catabolize the inositol-5-pyrophosphates, and their simultaneous inactivation results in overaccumulation of 5-IP7. Cells lacking all three pyrophosphatases amass high levels of 1,5-IP8 and 1-IP7, with concomitant depletion of IP6. A genetic screen identified three missense mutations in the catalytic domain of Kcs1 kinase that suppressed inositol-1pyrophosphate toxicosis. The screen also implicated the 3'-processing factor Swd22, the inositol pyrophosphate sensor Spx1, and the nuclear poly(A)-binding protein Nab2 as mediators of inositol-1-pyrophosphate toxicity. Copyright © 2025 Schwer et al. |
| Keywords: | genetics; metabolism; phosphatase; enzymology; phosphoric monoester hydrolases; schizosaccharomyces; schizosaccharomyces pombe proteins; schizosaccharomyces pombe protein; schizosaccharomyces pombe; acid phosphatase; pyrophosphatases; inositol phosphate; pyrophosphate; diphosphates; inositol phosphates; inorganic pyrophosphatase; inositol pyrophosphates; asp1 protein, s pombe; multifunctional enzyme; multifunctional enzymes |
| Journal Title: | mBio |
| Volume: | 16 |
| Issue: | 5 |
| ISSN: | 2150-7511 |
| Publisher: | American Society for Microbiology |
| Date Published: | 2025-05-01 |
| Start Page: | e0038925 |
| Language: | English |
| DOI: | 10.1128/mbio.00389-25 |
| PUBMED: | 40237466 |
| PROVIDER: | scopus |
| PMCID: | PMC12077094 |
| DOI/URL: | |
| Notes: | Article -- MSK corresponding author is Stewart Shuman -- Source: Scopus |
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