My interest for phosphate homeostasis and the function of highly phosphorylated molecules (inositol polyphosphateand inorganic polyphosphate) started during my first postdoc when I was working on membrane trafficking at the University of Lausanne (Switzerland)(see below). I then decided to move to a lab with theoretical and experimental expertise in phosphate homeostasis and energy metabolism. I am now working in the lab of Adolfo Saiardi at University College London (MRC LMCB).
My research brings together metabolism and signalling and focuses on how eukaryotic cells sense intracellular phosphate, how they deal with phosphate stores, and how they regulate the size of the different phosphate pools (inositol polyphosphate, inorganic polyphosphate, nucleotides pool, free phosphate). I am using two model systems to tackle the problem: yeast (Saccharomyces cerevisiae, Schizosaccharomyces pombe) and the social amoebaDictyostelium discoideum.
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SPX domains control phosphate homeostasis in eukaryotes. Ten genes in yeast encode SPX-containing proteins, among which YDR089W is the only one of unknown function. Here, we show that YDR089W encodes a novel subunit of the Vacuole Transporter Chaperone (VTC) complex that produces inorganic polyphosphate (polyP). PolyP synthesis transfers inorganic phosphate (Pi) from the cytosol into the acidocalcisome- and lysosome-related vacuoles of yeast, from where it can be released again. It was hence proposed to buffer changes in cytosolic Pi concentration (1). Vtc5 physically interacts with the VTC complex and accelerates the accumulation of polyP synthesized by it go to this site. Deletion of VTC5 reduces polyP accumulation in vivo and in vitro. Its overexpression hyper-activates polyP production and triggers the phosphate starvation response via the PHO pathway. Since this Vtc5-induced starvation response can be reverted by shutting down polyP synthesis genetically or pharmacologically, we propose that polyP synthesis rather than Vtc5 itself is a regulator of the PHO pathway. Our observations suggest that polyP synthesis not only serves to establish a buffer for transient drops in cytosolic Pi levels, but that it can actively decrease or increase the steady state of cytosolic Pi.
Cells control the size of their compartments relative to cell volume, but there is also size control within each organelle. Yeast vacuoles neither burst nor do they collapse into a ruffled morphology, indicating that the volume of the organellar envelope is adjusted to the amount of content. It is poorly understood how this adjustment is achieved. We show that the accumulating content of yeast vacuoles activates fusion of other vacuoles, thus increasing the volume-to-surface ratio. Synthesis of the dominant compound stored inside vacuoles, polyphosphate, stimulates binding of the chaperone Sec18/NSF to vacuolar SNAREs, which activates them and triggers fusion. SNAREs can only be activated by lumenal, not cytosolic, polyphosphate (polyP). Control of lumenal polyP over SNARE activation in the cytosol requires the cytosolic cyclin-dependent kinase Pho80-Pho85 and the R-SNARE Nyv1. These results suggest that cells can adapt the volume of vacuoles to their content through feedback from the vacuole lumen to the SNAREs on the cytosolic surface of the organelle.
How proteins migrate through the interconnected organelles of the endolysosomal system is poorly understood. A piece of the puzzle has been added with the identification of a complex of tethering factors that functions in the recycling of proteins towards the cell surface.