Versatile roles of inositol hexakisphosphate in the ubiquitin-proteasome system

Inositol hexakisphosphate (IP6) is an endogenous organic molecule present in eukaryotes. First characterized as a phosphorus-storage metabolite, it has been subsequently discovered to play a role in modulating a multitude of different biological pathways. Here, we provide a concise overview of the involvement of IP6 in the ubiquitin-proteasome system (UPS). As an allosteric regulator, a molecular glue, and a potential prosthetic group, IP6 directly impacts the activities of multiple major UPS components. We specifically highlight the structural mechanisms through which IP6 binds to individual proteins or multi-protein complexes to control their functions. The serendipitous discovery of IP6 in various protein structures raises questions about the prevalence, identity, and regulation of soluble inositol polyphosphates in the UPS, which have potential translational implications.