Inositol polyphosphates intersect with signaling and metabolic networks via two distinct mechanisms

Proc Natl Acad Sci U S A. 2016 Nov 1;113(44):E6757-E6765. doi: 10.1073/pnas.1606853113. Epub 2016 Oct 19.


Inositol-based signaling molecules are central eukaryotic messengers and include the highly phosphorylated, diffusible inositol polyphosphates (InsPs) and inositol pyrophosphates (PP-InsPs). Despite the essential cellular regulatory functions of InsPs and PP-InsPs (including telomere maintenance, phosphate sensing, cell migration, and insulin secretion), the majority of their protein targets remain unknown. Here, the development of InsP and PP-InsP affinity reagents is described to comprehensively annotate the interactome of these messenger molecules. By using the reagents as bait, >150 putative protein targets were discovered from a eukaryotic cell lysate (Saccharomyces cerevisiae). Gene Ontology analysis of the binding partners revealed a significant overrepresentation of proteins involved in nucleotide metabolism, glucose metabolism, ribosome biogenesis, and phosphorylation-based signal transduction pathways. Notably, we isolated and characterized additional substrates of protein pyrophosphorylation, a unique posttranslational modification mediated by the PP-InsPs. Our findings not only demonstrate that the PP-InsPs provide a central line of communication between signaling and metabolic networks, but also highlight the unusual ability of these molecules to access two distinct modes of action.

Keywords: affinity reagents; inositol pyrophosphates; metabolism; protein pyrophosphorylation; signal transduction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Diphosphates / metabolism
  • Eukaryotic Cells / metabolism
  • Glucose / metabolism
  • Inositol Phosphates / metabolism*
  • Magnesium
  • Metabolic Networks and Pathways / physiology*
  • Nucleotides / metabolism
  • Phosphorylation
  • Polyphosphates / metabolism*
  • Proteome
  • Ribosomes / metabolism
  • Saccharomyces cerevisiae / metabolism
  • Signal Transduction / physiology*


  • Diphosphates
  • Inositol Phosphates
  • Nucleotides
  • Polyphosphates
  • Proteome
  • Magnesium
  • Glucose