Asp1 Bifunctional Activity Modulates Spindle Function via Controlling Cellular Inositol Pyrophosphate Levels in Schizosaccharomyces pombe

Mol Cell Biol. 2018 Apr 16;38(9):e00047-18. doi: 10.1128/MCB.00047-18. Print 2018 May 1.

Abstract

The generation of two daughter cells with the same genetic information requires error-free chromosome segregation during mitosis. Chromosome transmission fidelity is dependent on spindle structure/function, which requires Asp1 in the fission yeast Schizosaccharomyces pombe Asp1 belongs to the diphosphoinositol pentakisphosphate kinase (PPIP5K)/Vip1 family which generates high-energy inositol pyrophosphate (IPP) molecules. Here, we show that Asp1 is a bifunctional enzyme in vivo: Asp1 kinase generates specific IPPs which are the substrates of the Asp1 pyrophosphatase. Intracellular levels of these IPPs directly correlate with microtubule stability: pyrophosphatase loss-of-function mutants raised Asp1-made IPP levels 2-fold, thus increasing microtubule stability, while overexpression of the pyrophosphatase decreased microtubule stability. Absence of Asp1-generated IPPs resulted in an aberrant, increased spindle association of the S. pombe kinesin-5 family member Cut7, which led to spindle collapse. Thus, chromosome transmission is controlled via intracellular IPP levels. Intriguingly, identification of the mitochondrion-associated Met10 protein as the first pyrophosphatase inhibitor revealed that IPPs also regulate mitochondrial distribution.

Keywords: PPIP5K family; Schizosaccharomyces pombe; chromosome segregation; inositol pyrophosphate; microtubule; mitosis; phosphatase; signaling molecules; yeast.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosome Segregation / physiology
  • Cytoskeletal Proteins / metabolism*
  • Cytoskeletal Proteins / physiology*
  • Inositol
  • Inositol Phosphates / metabolism
  • Inositol Phosphates / physiology
  • Kinesin / metabolism
  • Microtubule-Associated Proteins
  • Microtubules
  • Mitosis / physiology
  • Phosphotransferases (Phosphate Group Acceptor) / metabolism
  • Schizosaccharomyces
  • Schizosaccharomyces pombe Proteins / metabolism*
  • Schizosaccharomyces pombe Proteins / physiology*
  • Spindle Apparatus / metabolism*
  • Spindle Apparatus / physiology
  • Sulfite Reductase (NADPH) / metabolism

Substances

  • Asp1 protein, S pombe
  • Cut7 protein, S pombe
  • Cytoskeletal Proteins
  • Inositol Phosphates
  • Microtubule-Associated Proteins
  • Schizosaccharomyces pombe Proteins
  • Inositol
  • Sulfite Reductase (NADPH)
  • Phosphotransferases (Phosphate Group Acceptor)
  • diphosphoinositol pentakisphosphate kinase
  • Kinesin