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Illuminating the functions, cellular locations and regulation of inositol pyrophosphate nutrient messengers

Applicant Hothorn Michael
Number 209412
Funding scheme Sinergia
Research institution Département de Biologie Végétale Faculté des Sciences Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Interdisciplinary
Start/End 01.07.2022 - 30.06.2026
Approved amount 2'858'193.00
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All Disciplines (8)

Discipline
Interdisciplinary
Genetics
Cellular Biology, Cytology
Organic Chemistry
Biochemistry
Botany
Biophysics
Other disciplines of Physics

Keywords (17)

signal transduction; X-ray protein crystallography; plant genetics; yeast cell biology; yeast genetics; machine learning; transcription factors; inositol pyrophosphates; NMR spectroscopy; cryo electron microscopy; organic chemistry; quantitative biochemistry; yeast biochemistry; image processing; crop science; phosphate homeostasis; genome editing

Lay Summary (German)

Lead
Phosphor ist ein wichtiger Baustein des Lebens, der von Zellen für die Synthese von verschiedenen Biomolekülen, als Energiespeicher und als Signalmolekül verwendet wird. Organismen müssen daher Phosphor als Phosphat aufnehmen und speichern um immer ausreichend Phosphor zur Verfügung zu haben. Inositolpyrophosphate sind Nährstoff-Botenstoffe, die viel Phosphor enthalten und die Zelle darüber informieren, ob ausreichend Phosphor für die verschiedenen zellulären Aufgaben vorhanden ist.
Lay summary

Ziel unseres interdisziplinären Forschungsvorhaben ist es besser zu verstehen, wie die Inositolpyrophosphate hergestellt und abgebaut werden, und welche Signalwirkung sie in Zellen entfalten können. Wir möchten zudem Biosensoren für Inositolpyrophosphate entwickeln, um diese Botenstoffe in lebenden Organismen indirekt sichtbar machen zu können. Das wird uns helfen ihre verschiedenen Funktionen in Wachstum und Entwicklung zu verstehen, zum Beispiel im Hinblick auf die Proteinbiosynthese. Schlussendlich wollen wir den Auf- und Abbau von Inositolpyrophosphaten in verschiedenen Pflanzenarten leicht verändern. Wir hoffen damit langfristig neue Varianten von Nutzpflanzen erzeugen zu können, welche mit weniger Phosphatdünger im Boden auskommen.

Direct link to Lay Summary Last update: 08.06.2022

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
170925 Discovery and mechanistic dissection of novel signaling pathways controlling phosphate homeostasis in eukaryotes 01.01.2017 Sinergia

Abstract

Phosphorus is an essential building block of many biomolecules that serve diverse structural, metabolic and signaling roles. It is taken up by cells in the form of inorganic phosphate (Pi). Plants take up Pi from the soil, where Pi is abundant but poorly bioavailable. In our previous Sinergia grant (170925), we have characterized a signaling pathway that enables plants to maintain cellular Pi levels and to trigger Pi starvation responses when Pi becomes limiting. At the heart of the pathway are inositol pyrophosphate messengers (PP-InsPs), which enable cells to sense and regulate cellular Pi levels. In plants, animals and fungi bifunctional diphosphoinositol pentakisphosphate kinases /phosphatases (PPIP5Ks) generate and break down the metabolic messenger 1,5-bis-diphosphoinositol tetrakisphosphate (1,5(PP)2-InsP4 or InsP8). Under Pi-sufficient growth conditions, cellular ATP and Pi levels stimulate the kinase and inhibit the phosphatase activity of PPIP5Ks leading to InsP8 accumulation. InsP8 next binds to the PP-InsP receptor protein SPX. In plants, the InsP8-bound SPX receptor can interact with transcription factors, keeping them from binding to target promoters. In contrast, Pi starvation reduces cellular ATP and Pi levels, inhibiting the kinase and stimulating the phosphatase of plant PPIP5Ks. InsP8 levels drop, SPX - transcription factor complexes dissociate, and the released transcription factors trigger the Pi starvation response. Phosphate rock, the source material of our modern Pi fertilizers, is currently consumed at an alarming scale. We now propose to elevate our mechanistic and physiological understanding of plant and microbial PP-InsP signaling and of Pi starvation responses to aid the engineering of Pi starvation tolerant plants. Such plants will allow reduction of Pi fertilizer use and will enable to maintain or further improve crop yields in a rapidly changing climate, on less and less farmable land. Specifically, we aim: (1) to uncover the molecular mechanism of eukaryotic PPIP5K regulation using a combination of chemical tools, structural biology, in vivo and in vitro biochemistry, and yeast & plant genetics.(2) to develop biosensors for specific PP-InsP isoforms and apply them to quantitatively study Pi sensing and nutrient starvation responses in yeast cells, and in plant tissues by combining cell biology and physiology with machine-learning based image analysis.(3) to identify novel PP-InsP regulated nutrient signaling responses in forward genetic screens. We will mechanistically characterize screen candidates, which for example are involved in ribosome biogenesis, by integrating structural biology and quantitative biochemistry with cell biology and genetics.(4) to apply the knowledge gained towards the engineering of model (Marchantia polymorpha, Arabidopsis) and crop (rice) plants with altered PP-InsP metabolism, Pi sensing/signaling and Pi starvation responses, by combining structure-guided protein engineering with reverse genetics and genome editing, and with automated phenotyping.
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