Discussion

Yeast lacking the IP6 kinase Kcs1, which have no detectable IP7 and IP8, show sensitivity to translation inhibitors. However, yeast that possess even one form of inositol pyrophosphate, i.e. vip1Δ yeast that have 5-IP7, or kcs1Δddp1Δ yeast that have 1-IP7, display a normal phenotype. 5-IP7 is the product of Kcs1 whereas 1-IP7 is the product of Vip1. 5-IP7 and 1-IP7 can regulate protein function in two ways: 1) direct binding to proteins to modulate their function. For example, 1-IP7 binds to Pho80Pho85-Pho81 complex in yeast and regulates phosphate metabolism, but 5-IP7 cannot perform this function (Lee et al., 2008), and 5-IP7 binds and regulates CK2 in mammals (Rao et al., 2014); 2) by transferring their β phosphate to pre-phosphorylated serine residues on proteins, bringing about the post-translational modification of pyrophosphorylation. For example, 5-IP7 pyrophosphorylates the yeast transcription factor Gcr1 thereby regulating transcription of glycolytic enzymes (Szijgyarto et al., 2011), and pyrophosphorylation of the adaptor protein AP3β by 5-IP7 regulates vesicle trafficking in mammalian cells (Azevedo et al., 2009). Protein pyrophosphorylation can be brought about by 5-IP7, 1-IP7 and IP8 (Bhandari et al., 2007). Therefore, modulation of protein function by pyrophosphorylation is a cumulative effect of all cellular inositol pyrophosphates, whereas functions that are specific to individual inositol pyrophosphates depend on protein binding. The mode of action of IP7 can therefore vary in the regulation of different signalling pathways.