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Discovery and mechanistic dissection of novel signaling pathways controlling phosphate homeostasis in eukaryotes

Applicant Hothorn Michael
Number 170925
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 01.01.2017 - 30.06.2021
Approved amount 2'405'109.00
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All Disciplines (7)

Discipline
Interdisciplinary
Cellular Biology, Cytology
Biophysics
Organic Chemistry
Biochemistry
Genetics
Botany

Keywords (11)

plant genetics; transcription factors; protein dynamics; signal transduction; NMR spectroscopy; phosphate homeostasis; X-ray protein crystallography; G-protein signalling; yeast genetics; inositol pyrophosphates; organic chemistry

Lay Summary (German)

Lead
Kontrolle des Phosphathaushalts in höheren Lebewesen durch Inositolpyrophosphat-abhängige SignalwegeDas chemische Element Phosphor ist ein essentieller Baustein unseres Erbguts, unserer Zellmembranen, die Energiewährung unseres Stoffwechsels und ein wichtiges Signalmolekül. Phosphor liegt in der Natur als Phosphat vor und wird von Pflanzen und Mikroorganismen aus dem Boden aufgenommen. Da die verfügbare Menge an Phosphat in vielen Böden gering ist, haben sich komplizierte Systeme zur Phosphataufnahme gebildet. Woher ein Organismus allerdings weiß, ob er genug Phosphat aufgenommen hat, ist bislang unbekannt.
Lay summary

Inhalte und Ziele des Forschungsprojekts

Viele Eiweiße, die für die Aufnahme, den Transport, und die Speicherung von Phosphat verantwortlich sind, enthalten SPX Domänen. Wir konnten kürzlich zeigen, dass SPX Domänen zelluläre Rezeptoren für Inositolpyrophosphate sind. Diese Signalmoleküle weisen eine Ringstruktur auf, an denen eine Vielzahl von Phosphatgruppen angeheftet sind. Die Konzentration von Inositolpyrophosphaten ist hoch in Zellen, welche genügend Phosphat aus ihrer Umgebung aufnehmen können. Unter Phosphatmangel jedoch, nimmt die Konzentration von Inositolpyrophosphaten stark ab. Dies hat zur Folge, dass unter guten Wachstumsbedingungen eine SPX Domäne als Komplex mit einem Inositolpyrophosphat vorliegt, in diesem Zustand andere Eiweiße binden, und so die Funktion dieser Zielproteine regulieren kann. Bei Phosphatmangel dissoziieren diese Komplexe, und die Zielproteine können andere Funktionen wahrnehmen. In unserem Projekt wollen wir herausfinden, wie die Konzentration von Inositolpyrophosphaten gesteuert wird, welche Zielproteine erkannt werden, und wie diese Interaktionen den Phosphathaushalt regulieren.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Durch die Erforschung der grundlegenden Prinzipien werden wir die Ernährung von Pilzen und Pflanzen unter wechselnden Umweltbedingungen besser verstehen. Unsere Arbeit kann so die Grundlagen für die Entwicklung von neuen, auf phosphatarme Böden angepasste Nutzpflanzen liefern.

Direct link to Lay Summary Last update: 07.12.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Inositol pyrophosphates promote the interaction of SPX domains with the coiled-coil motif of PHR transcription factors to regulate plant phosphate homeostasis
Ried Martina K., Wild Rebekka, Zhu Jinsheng, Pipercevic Joka, Sturm Kristina, Broger Larissa, Harmel Robert K., Abriata Luciano A., Hothorn Ludwig A., Fiedler Dorothea, Hiller Sebastian, Hothorn Michael (2021), Inositol pyrophosphates promote the interaction of SPX domains with the coiled-coil motif of PHR transcription factors to regulate plant phosphate homeostasis, in Nature Communications, 12(1), 384-384.
Affinity enrichment and identification of inositol poly- and pyrophosphate interactomes
Furkert David, Nadler-Holly Michal, Fiedler Dorothea (2021), Affinity enrichment and identification of inositol poly- and pyrophosphate interactomes, in STAR Protocols, 2(1), 100277-100277.
New structural insights reveal an expanded reaction cycle for inositol pyrophosphate hydrolysis by human DIPP1
Zong Guangning, Jork Nikolaus, Hostachy Sarah, Fiedler Dorothea, Jessen Henning J., Shears Stephen B., Wang Huanchen (2021), New structural insights reveal an expanded reaction cycle for inositol pyrophosphate hydrolysis by human DIPP1, in The FASEB Journal, 35(2), 1-10.
Dissecting the activation of insulin degrading enzyme by inositol pyrophosphates and their bisphosphonate analogs
Hostachy Sarah, Utesch Tillmann, Franke Katy, Dornan Gillian Leigh, Furkert David, Türkaydin Berke, Haucke Volker, Sun Han, Fiedler Dorothea (2021), Dissecting the activation of insulin degrading enzyme by inositol pyrophosphates and their bisphosphonate analogs, in Chemical Science, 1-10.
The inositol pyrophosphate 5-InsP 7 drives sodium-potassium pump degradation by relieving an autoinhibitory domain of PI3K p85α
Chin Alfred C., Gao Zhe, Riley Andrew M., Furkert David, Wittwer Christopher, Dutta Amit, Rojas Tomas, Semenza Evan R., Felder Robin A., Pluznick Jennifer L., Jessen Henning J., Fiedler Dorothea, Potter Barry V. L., Snyder Solomon H., Fu Chenglai (2020), The inositol pyrophosphate 5-InsP 7 drives sodium-potassium pump degradation by relieving an autoinhibitory domain of PI3K p85α, in Science Advances, 6(44), eabb8542-eabb8542.
IP 7 -SPX Domain Interaction Controls Fungal Virulence by Stabilizing Phosphate Signaling Machinery
Desmarini Desmarini, Lev Sophie, Furkert David, Crossett Ben, Saiardi Adolfo, Kaufman-Francis Keren, Li Cecilia, Sorrell Tania C., Wilkinson-White Lorna, Matthews Jacqueline, Fiedler Dorothea, Djordjevic Julianne Teresa (2020), IP 7 -SPX Domain Interaction Controls Fungal Virulence by Stabilizing Phosphate Signaling Machinery, in mBio, 11(5), 1-10.
InsP 7 is a small-molecule regulator of NUDT3-mediated mRNA decapping and processing-body dynamics
Sahu Soumyadip, Wang Zhenzhen, Jiao Xinfu, Gu Chunfang, Jork Nikolaus, Wittwer Christopher, Li Xingyao, Hostachy Sarah, Fiedler Dorothea, Wang Huanchen, Jessen Henning J., Kiledjian Megerditch, Shears Stephen B. (2020), InsP 7 is a small-molecule regulator of NUDT3-mediated mRNA decapping and processing-body dynamics, in Proceedings of the National Academy of Sciences, 117(32), 19245-19253.
Triplexed Affinity Reagents to Sample the Mammalian Inositol Pyrophosphate Interactome
Furkert David, Hostachy Sarah, Nadler-Holly Michal, Fiedler Dorothea (2020), Triplexed Affinity Reagents to Sample the Mammalian Inositol Pyrophosphate Interactome, in Cell Chemical Biology, 27(8), 1097-1108.e4.
Control of XPR1-dependent cellular phosphate efflux by InsP 8 is an exemplar for functionally-exclusive inositol pyrophosphate signaling
Li Xingyao, Gu Chunfang, Hostachy Sarah, Sahu Soumyadip, Wittwer Christopher, Jessen Henning J., Fiedler Dorothea, Wang Huanchen, Shears Stephen B. (2020), Control of XPR1-dependent cellular phosphate efflux by InsP 8 is an exemplar for functionally-exclusive inositol pyrophosphate signaling, in Proceedings of the National Academy of Sciences, 117(7), 3568-3574.
Two bifunctional inositol pyrophosphate kinases/phosphatases control plant phosphate homeostasis
Zhu Jinsheng, Lau Kelvin, Puschmann Robert, Harmel Robert K, Zhang Youjun, Pries Verena, Gaugler Philipp, Broger Larissa, Dutta Amit K, Jessen Henning J, Schaaf Gabriel, Fernie Alisdair R, Hothorn Ludwig A, Fiedler Dorothea, Hothorn Michael (2019), Two bifunctional inositol pyrophosphate kinases/phosphatases control plant phosphate homeostasis, in eLife, 8, 1-25.

Collaboration

Group / person Country
Types of collaboration
Roberto Docampo/University of Georgia United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Henning Jessen/Universität Freiburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Adolfo Saiardi/MRC and University College London Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
FEBS PP-InsP virtual meeting Talk given at a conference Inositol pyrophosphate controlled phosphate starvation responses in plants 11.01.2021 Cadiz, Spain Hothorn Michael;
HHMI investigator meeting Talk given at a conference Zooming in and out on inositol pyrophosphate signaling networks 26.09.2018 Bethesda, United States of America Hothorn Michael;
PSP6 meeting Talk given at a conference Inositol pyrophosphates control eukaryotic phosphate homeostasis by binding to SPX sensor domains 11.09.2018 Leuven, Belgium Hothorn Michael;
International Conference on Arabidopsis Research (ICAR) Talk given at a conference Inositol pyrophosphate signaling molecules control plant phosphate homeostasis by binding to SPX sensor domains 19.06.2017 St. Louis, United States of America Hothorn Michael;


Awards

Title Year
HHMI International Research Scholar 2017

Associated projects

Number Title Start Funding scheme
176237 Plant membrane receptor kinase complexes and their connection to cytoplasmic signaling cascades 01.10.2017 Project funding (Div. I-III)
185388 Biophysical Principles of Chaperone-Client Interactions 01.08.2019 Project funding (Div. I-III)

Abstract

Inorganic phosphate (Pi) is an essential and limiting nutrient for all eukaryotes. The cytosolic concentration of Pi determines the energetics of metabolic reactions that use, for example, ATP. Hydrolysis of its phosphoanhydride bonds can only provide sufficient energy to drive metabolic reactions if cytosolic Pi concentrations remain low. At the same time, the cytosol must provide sufficient Pi to allow for the synthesis of DNA, RNA, membranes and the phosphorylation of proteins and metabolites. Therefore, cells tightly control cytosolic Pi levels. Here, we propose to elucidate novel signal transduction pathways that mediate this control and study the properties of their key components in mechanistic detail.Cytosolic Pi concentrations depend on the activity of membrane-localized Pi importers and exporters, and on enzymes storing or consuming Pi, many of which contain SPX domains. We have recently uncovered that these domains represent cellular sensors for inositol pyrophosphates (PP-InsPs), a class of eukaryotic signaling molecules whose concentrations change in response to Pi availability. PP-InsPs bind to a conserved basic surface patch in SPX and render the domain competent to interact with down-stream signaling partners, for example Pi starvation responsive transcription factors in plants. Thus, PP-InsPs appear to communicate cytosolic Pi levels via SPX domains to a multitude of proteins to regulate Pi uptake, transport and storage.We now want to combine organic chemistry, biophysics, biochemistry and genetics to uncover the PP-InsP-controlled Pi signaling pathways in plants and in yeast. Specifically, we propose to study how PP-InsP binding affects SPX protein dynamics, allowing the domain to interact with and regulate down-stream target proteins. We will develop synthetic strategies to produce matrix-coupled PP-InsPs to affinity-purify stereoisomer-specific signaling complexes from yeast cells and different plant tissues. We will also design novel PP-InsP variants to allow for covalent trapping of low affinity and/or low-abundance PP-InsP-containing protein complexes. Forward and reverse genetic screens in Arabidopsis and in yeast will be used to uncover further elements of these Pi signaling pathways. Finally, we aim to dissect how changing Pi levels are translated into changes of PP-InsP concentrations in plant and yeast cells.Our integrated approach will likely uncover previously uncharacterized signaling cascades for intracellular Pi homeostasis in mechanistic detail and produce novel chemical and genetic tools to study Pi signaling. An exciting future application of our work may be the creation of transgenic crops with optimized Pi metabolism.
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