Inositol Pyrophosphate-Controlled Kinetochore Architecture and Mitotic Entry in S. pombe

Inositol pyrophosphates (IPPs) comprise a specific class of signaling molecules that regulate central biological processes in eukaryotes. The conserved Vip1/PPIP5K family controls intracellular IP₈ levels, the highest phosphorylated form of IPPs present in yeasts, as it has both inositol kinase and pyrophosphatase activities. Previous studies have shown that the fission yeast S. pombe Vip1/PPIP5K family member Asp1 impacts chromosome transmission fidelity via the modulation of spindle function. We now demonstrate that an IP₈ analogue is targeted by endogenous Asp1 and that cellular IP₈ is subject to cell cycle control. Mitotic entry requires Asp1 kinase function and IP₈ levels are increased at the G2/M transition. In addition, the kinetochore, the conductor of chromosome segregation that is assembled on chromosomes is modulated by IP₈. Members of the yeast CCAN kinetochore-subcomplex such as Mal2/CENP-O localize to the kinetochore depending on the intracellular IP₈-level: higher than wild-type IP₈ levels reduce Mal2 kinetochore targeting, while a reduction in IP₈ has the opposite effect. As our perturbations of the inositol polyphosphate and IPP pathways demonstrate that kinetochore architecture depends solely on IP₈ and not on other IPPs, we conclude that chromosome transmission fidelity is controlled by IP₈ via an interplay between entry into mitosis, kinetochore architecture, and spindle dynamics.