Cell signalling by inositol pyrophosphates
Lead Research Organisation:
University College London
Department Name: UNLISTED
Abstract
The cells of our body are required to communicate and coordinate external inputs, such as nutrient availability or hormone levels, in order to behave properly. In cells information is collected and spread through molecules, via changing of their amounts and locations. Loss of control of these complex cellular processes leads to pathological conditions and human diseases. We aim to understand how information is created, stored and communicated inside cells and throughout our bodies by studying a certain collection of these “signalling” molecules: the inositol phosphates. This family comprises a number of molecules that are found in all organisms, and are essential for correct cell health and behaviour. So far we know that inositol phosphates are involved in coordinating the use of the important nutrient phosphate, but we are still working to understand how this is achieved. The amounts and roles of inositol phosphates are altered in pathological conditions such as diabetes and obesity; the ultimate goal is to fix these problems at a cellular level, and thus help patients.
Technical Summary
Living cells are required to communicate and coordinate external inputs and internal needs in order to behave appropriately. Intracellular cell signalling networks coordinate cellular physiology by integrating and disseminating information. Understanding how this information is elaborated, stored and transduced represents one of the most fascinating aspects of biology. Inositol phosphates (IP), found as both lipid-bound and cytosolic isoforms, represent one of the most complex cell signalling systems. We are studying the inositol phosphate network with the aim of understanding the molecular logic of cellular signalling. Investigation into cellular regulation by IP has yielded surprising knowledge that reaches well beyond the established roles of IP3 (as calcium releasing factor) and PIP3 (as AKT activator). Indeed, I am interested in studying the numerous ‘non-classical’ aspects of the IP regulatory system. My primary interest is in the inositol pyrophosphates (PP-IPs), molecules which have not yet been fully characterised but are known to contain a high energetic pyrophosphate moiety, that are important controllers of cellular homeostasis and energetic metabolism. In comparison to the IP3/calcium or PIP3/AKT signalling paradigms, PP-IPs signalling is evolutionarily ancient, present in all eukaryotic organisms. The past ten years of research have positioned PP-IPs at the interface between metabolism and signalling, indicating that they are involved in the pathogenesis of important metabolic disorders like obesity and diabetes. Inositol pyrophosphates, by altering phosphate homeostasis, affect basic energetic metabolism and the synthesis of ATP and other phosphate-rich molecules such as inorganic polyphosphates (polyP). In spite of their clear relevance for a number of fundamental cellular functions, many aspects of the PP-IPs mode operandi remain poorly understood. Our research aims to fill this gap in knowledge by investigating how PP-IP levels are regulated, and elucidating the cross-talk between PP-IPs, polyP and ATP.
To appreciate the importance of PP-IPs and of the complex IP signalling system in general, we should realise that the entire IP network of molecules is metabolically connected. Therefore, understanding how this network of molecules evolved and became one of the fundamental signalling systems of eukaryotic cells may also help us understand the evolutionary pressures that created us.
To appreciate the importance of PP-IPs and of the complex IP signalling system in general, we should realise that the entire IP network of molecules is metabolically connected. Therefore, understanding how this network of molecules evolved and became one of the fundamental signalling systems of eukaryotic cells may also help us understand the evolutionary pressures that created us.
Organisations
People |
ORCID iD |
Adolfo Saiardi (Principal Investigator) |
Publications
Desmarini D
(2020)
IP7-SPX Domain Interaction Controls Fungal Virulence by Stabilizing Phosphate Signaling Machinery.
in mBio
Desfougères Y
(2020)
Inorganic polyphosphate in mammals: where's Wally?
in Biochemical Society transactions
Desfougères Y
(2020)
Dictyostelium discoideum as a Model to Study Inositol Polyphosphates and Inorganic Polyphosphate.
in Methods in molecular biology (Clifton, N.J.)
Riemer E
(2021)
ITPK1 is an InsP6/ADP phosphotransferase that controls phosphate signaling in Arabidopsis.
in Molecular plant
Mallery DL
(2021)
A stable immature lattice packages IP6 for HIV capsid maturation.
in Science advances
Kuenzel NA
(2022)
Inositol Pyrophosphate-Controlled Kinetochore Architecture and Mitotic Entry in S. pombe.
in Journal of fungi (Basel, Switzerland)
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00012/1 | 01/04/2017 | 31/03/2022 | £1,079,000 | ||
MC_UU_00012/2 | Transfer | MC_UU_00012/1 | 01/04/2017 | 31/03/2022 | £989,000 |
MC_UU_00012/3 | Transfer | MC_UU_00012/2 | 01/04/2017 | 31/03/2022 | £925,000 |
MC_UU_00012/4 | Transfer | MC_UU_00012/3 | 01/04/2017 | 31/03/2022 | £908,000 |
MC_UU_00012/5 | Transfer | MC_UU_00012/4 | 01/04/2017 | 31/03/2022 | £1,560,000 |
MC_UU_00012/6 | Transfer | MC_UU_00012/5 | 01/04/2017 | 31/03/2022 | £1,234,000 |
MC_UU_00012/7 | Transfer | MC_UU_00012/6 | 01/04/2017 | 31/03/2022 | £1,070,000 |
Description | Functional characterization of a new, evolutionarily conserved myo-inositol-hexakis-phosphate kinase in mammalian cells (Funktionelle Charakterisierung einer neuen, evolutiv konservierten myo -Inositol-Hexakis-Phosphat Kinase in Säugerzellen) |
Amount | € 170,000 (EUR) |
Organisation | German Research Foundation |
Sector | Charity/Non Profit |
Country | Germany |
Start | 07/2019 |
End | 06/2021 |
Description | Marie Curie Intra-European Fellowships |
Amount | € 195,454 (EUR) |
Funding ID | EU project 752903 - PHEMDD - GAP-752903 |
Organisation | Marie Sklodowska-Curie Actions |
Sector | Charity/Non Profit |
Country | Global |
Start | 07/2017 |
End | 07/2019 |
Description | Developing inositol phosphate chemical tools |
Organisation | University of Zurich |
Country | Switzerland |
Sector | Academic/University |
PI Contribution | Developing inositol phosphate chemical tools |
Collaborator Contribution | organic synthesis |
Impact | One publication Pavlovic I, Thakor DT, Bigler L, Wilson MS, Laha D, Schaaf G, Saiardi A, Jessen HJ. Prometabolites of 5-Diphospho-myo-inositol Pentakisphosphate. Angew Chem Int Ed Engl. 2015 Aug 10;54(33):9622-6. PMID: 26014370. |
Start Year | 2013 |
Description | Inositol phosphate and phosphate homeostasis in Dictyostelium discoideum |
Organisation | University College London |
Department | MRC Laboratory for Molecular Cell Biology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We developed Dictyostelium discoideum as a model to study inositol phosphate metabolism and the inorganic polyphosphate (polyP) role in biology. Our experience in inositol polyphosphate and polyP analysis have rapidly facilitated the development of this model thanks to the help of our collaborator. We are now using amoeba to understand the role of the cited molecules to control cellular phosphate homeostasis. |
Collaborator Contribution | He transferred his know-how on Amoeba biology to my laboratory personnel, furthermore, he has given us tools and reagents essential to initiate to perform Dictyostelium discoideum research. |
Impact | This collaboration generated two scientific publications: 1: Livermore TM, Chubb JR, Saiardi A. Developmental accumulation of inorganic polyphosphate affects germination and energetic metabolism in Dictyostelium discoideum. Proc Natl Acad Sci U S A. 2016 Jan 26;113(4):996-1001. 2: Pisani F, Livermore T, Rose G, Chubb JR, Gaspari M, Saiardi A. Analysis of Dictyostelium discoideum inositol pyrophosphate metabolism by gel electrophoresis. PLoS One. 2014 Jan 9;9(1):e85533. More importantly a postdoc of the laboratory proposing a project based on this collaboration was awarded a Marie Curie Fellowship (EU project 752903 - PHEMDD - GAP-752903) |
Start Year | 2013 |
Description | Inositol pyrophosphate signaling in the yeast S. pombe |
Organisation | Heinrich Heine University Düsseldorf |
Country | Germany |
Sector | Academic/University |
PI Contribution | Transfer of my inositol pyrophosphate and inorganic polyphosphate (polyP) theoretical and practical know-how. Biochemical analysis of Schizosaccharomyces pombe inositol kinases mutant strains. |
Collaborator Contribution | Initiated the project identifying by genetic studies key roles for inositol phosphate kinases of Schizosaccharomyces pombe, Is providing stains, expertise, tools and genetic analyses. |
Impact | This collaboration is just started, thus there are not output to be listed. However, a important publication has been just been accepted (Mol Cell Biol. 2018 Feb 12. pii: MCB.00047-18. doi: 10.1128/MCB.00047-18.) in wich we describe the importance of the phosphatase domain of PP-IP5K to regulate the level of inositol pyrophosphates. This collaboration is multidisciplinary, involving a yeast geneticist and a biochemist. |
Start Year | 2017 |
Description | Roles of Inositol Phosphates in Viral Biology |
Organisation | Medical Research Council (MRC) |
Department | MRC Laboratory of Molecular Biology (LMB) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Our inositol phosphate analysis technologies allow us to analyse the inositol phosphate levels in HIV virion. We are also theoretically contributing to this collaborative project by transferring our unique inositol metabolic pathways know-own. |
Collaborator Contribution | The partner is a HIV structural biologist and bring in this collaboration the HIV biology expertise |
Impact | This collaboration is multidisciplinary, involving a structural biologist/ immunologist and a biochemist. This collaboration generated a published paper and a second manuscript just submitted. IP6 is an HIV pocket factor that prevents capsid collapse and promotes DNA synthesis. Mallery DL, et al. Elife. 2018 May 31;7. pii: e35335. |
Start Year | 2017 |
Description | plant inositol pyrophosphate |
Organisation | Eberhard Karls University of Tübingen |
Country | Germany |
Sector | Academic/University |
PI Contribution | analysis of inositol phosphate levels excenge of reagent and tecnologies |
Collaborator Contribution | developing the research line and generating plant mutant lines |
Impact | One publication VIH2 Regulates the Synthesis of Inositol Pyrophosphate InsP8 and Jasmonate-Dependent Defenses in Arabidopsis. Laha D, Johnen P, Azevedo C, Dynowski M, Weiß M, Capolicchio S, Mao H, Iven T, Steenbergen M, Freyer M, Gaugler P, de Campos MK, Zheng N, Feussner I, Jessen HJ, Van Wees SC, Saiardi A, Schaaf G. Plant Cell. 2015 Apr;27(4):1082-97. |
Start Year | 2013 |
Title | IP6K1/2-/- HCT116 Human Colon Carcinoma Cell Line |
Description | We created several cell lines with altered inositol pyrophosphate metabolism The cell lines were originally described in: J Biol Chem. 2019 Jul 26;294(30):11597-11608. doi: 10.1074/jbc.RA119.007848 |
IP Reference | |
Protection | Protection not required |
Year Protection Granted | 2019 |
Licensed | Yes |
Impact | We licensed IP6K1-/- and IP6K2-/- double-knockout as well as the IP6K1-/- and IP6K2-/- single knockout cell lines, generated in the HCT116 Human Colon Carcinoma Cell, to Applied Biological Materials Inc. (Richmond BC, Canada V6V 2J5) |
Description | Interview for national news on immortality |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | The radio programme discussed life after death. Dr. Miranda Wilson (Postdoc of the laboratory) was interviewed for a section on HeLa and other cell lines being a form of immortality. |
Year(s) Of Engagement Activity | 2017 |
URL | http://www.bbc.co.uk/programmes/w3csv3f3 |
Description | TEDx theme Brain Drain (23 February 2017, Cosenza, Italy) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | The different presentation focused on the Brain Drain that Italy is witnessing in recent years. I presented my experience and outline the difference approach to science and to scientist that exist in different part of the world. I also discuss the concept that "Science is not a democracy" something that the general public found difficult to accept. |
Year(s) Of Engagement Activity | 2017 |
URL | https://www.ted.com/tedx/events/19418 |