Inorganic polyphosphate (polyP), a linear polymer of dozens to thousands of orthophosphate units, has been found in virtually every pro- and eukaryotic cell. PolyP regulates blood clotting, inflammation and bone formation in humans, symbiotic interactions in plants and stress responses in bacteria. The molecular functions of this high-energy polymer however remain largely enigmatic and its synthesis has only been characterized in prokaryotes. Systematic investigation of polyP functions in higher organisms has so far been hampered by our complete lack of knowledge about the molecular machinery required for polyP synthesis, transport, storage and signalling. Here, I propose a multi-disciplinary approach to dissect the origins and functions of polyP in eukaryotes. Using a candidate approach, I have identified the polyP polymerase in Arabidopsis thaliana, and a closely related human enzyme. I propose to dissect the architecture and catalytic mechanism of the plant polyphosphate polymerase, and study its distribution in cells and tissues. Using genetics, we will next analyse the contribution of polyP synthesis to plant metabolism, growth and development. In parallel, we will develop biosensors to visualize the transport, storage and re-mobilisation of polyP in living cells. Together, these experiments should yield traceable phenotypes and novel tools that will enable us for the first time to design and evaluate polyP-specific genetic screens. By this means, we hope to identify other players involved in polyP metabolism, transport, storage, re-mobilisation and signalling. We will translate our findings from Arabidopsis to animal models, and study the evolution of this ancient polymer. I envision that our work will uncover a fundamental metabolic pathway, and may spur the design of crops that require less phosphate fertilizer, small molecule inhibitors against human parasites, and novel drugs that target inflammatory disease and osteoporosis.
Fields of science
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Funding SchemeERC-SG - ERC Starting Grant