Cell signalling by inositol pyrophosphates

Lead Research Organisation: University College London

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.

Publications

10 25 50

 
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 Public
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 Academic/University
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 (LMCB)
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 Public 
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 Tubingen
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
 
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