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 IP(8) 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 IP(8) analogue is targeted by endogenous Asp1 and that cellular IP(8) is subject to cell cycle control. Mitotic entry requires Asp1 kinase function and IP(8) 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 IP(8). Members of the yeast CCAN kinetochore-subcomplex such as Mal2/CENP-O localize to the kinetochore depending on the intracellular IP(8)-level: higher than wild-type IP(8) levels reduce Mal2 kinetochore targeting, while a reduction in IP(8) has the opposite effect. As our perturbations of the inositol polyphosphate and IPP pathways demonstrate that kinetochore architecture depends solely on IP(8) and not on other IPPs, we conclude that chromosome transmission fidelity is controlled by IP(8) via an interplay between entry into mitosis, kinetochore architecture, and spindle dynamics.