The promises of lysine polyphosphorylation as a regulatory modification in mammals are tempered by conceptual and technical challenges.

Polyphosphate (polyP) is a ubiquitous biomolecule thought to be present in all cells on Earth. PolyP is deceivingly simple, consisting of repeated units of inorganic phosphates polymerized in long energy-rich chains. PolyP is involved in diverse functions in mammalian systems-from cell signaling to blood clotting. One exciting avenue of research is a new nonenzymatic post-translational modification, termed lysine polyphosphorylation, wherein polyP chains are covalently attached to lysine residues of target proteins. While the modification was first characterized in budding yeast, recent work has now identified the first human targets. There is significant promise in this area of biomedical research, but a number of technical issues and knowledge gaps present challenges to rapid progress. In this review, the current state of the field is summarized and existing roadblocks related to the study of lysine polyphosphorylation in higher eukaryotes are introduced. It is discussed how limited methods to identify targets of polyphosphorylation are further impacted by low concentration, unknown regulatory enzymes, and sequestration of polyP into compartments in mammalian systems. Furthermore, suggestions on how these obstacles could be addressed or what their physiological relevance may be within mammalian cells are presented.