The Saiardi lab is interested in the intersection
between signalling and basic metabolism. Specifically we study the role played
by inositol pyrophosphates in maintaining cell homeostasis. Inositol
pyrophosphates are present in all eukaryotic cells and belong to the inositol
phosphates family of soluble signalling molecules. Both inositol phosphates and
inositol pyrophosphates are obtained by the combinatorial attachment of
phosphate groups to inositol. However, the inositol pyrophosphates are distinguished
by their one or more high-energy phosphoanhydride bonds (pyro- moieties). The
energy stored in these bonds provides the inositol pyrophosphates with the
potential to take part in new and not yet fully understood molecular actions. The
structure of these molecules and their conservation in eukaryotic biology suggests
a fundamental signalling role, acting through a unique mechanism.
Alteration of inositol pyrophosphate levels has
been associated with a wide collection of phenotypes as well as important human
pathology such as obesity, diabetes and cancer. These pleiotropic effects
suggest an ability to control a central cellular function. Our finding that
inositol pyrophosphates regulate intracellular levels of ATP places these
molecules at the interface between
signalling and basic metabolism.
We have developed three model systems with altered
inositol polyphosphate metabolism: the yeast Saccharomyces cerevisiae; the amoeba Dictyostelium discoideum; and a number of CRISPR-generated
mammalian cell lines. Each model allows us to investigate different aspects of
inositol pyrophosphate biology. We also endeavour to develop new technologies
for studying inositol pyrophosphate signalling. Our success so far in designing
novel methodologies has opened new research avenues in the field and drawn
further attention to these molecules.
We are currently directing our efforts towards developing techniques to allow localisation
of inositol pyrophosphates in cells. To achieve this important goal, the lab is
interested in the development of new probes and imaging technologies such as Raman
spectromicroscopy and multi-isotope imaging mass spectrometry (MIMS).
In our quest
to understand how inositol pyrophosphates regulate basic metabolism, we are studying
inorganic polyphosphate (polyP) biology. The phosphate chain of polyP represents
one of the simplest biological polymers but it is also one of the least
characterized. While many
specific signalling functions have been attributed to this ubiquitous polymer,
intrinsic to polyP’s structure is a fundamental role as cellular free phosphate
(Pi) buffer. In yeast, inositol pyrophosphates regulate the cellular
levels of polyP. We aim to extend these observations since phosphate homeostasis
is essential to cellular wellbeing. Understanding the metabolic link between
inositol pyrophosphates and polyP will help to elucidate how inositol
pyrophosphates regulate cellular metabolism. Additionally, our discovery of a
new protein post-translational modification consisting of the covalent
attachment of polyP to lysine residues (protein polyphosphorylation) has intensified
interest in polyP, offering a possible mechanism for the range of cellular
functions attributed to them.
Further to our primary focus
investigating the role played by inositol pyrophosphate in today’s cells, we
also pursue an academic interest in understanding how an ancient inositol
phosphate module with limited functions has evolved to become the sophisticated
system of signalling molecules present in our cells. Similarly, we are curious
how and why polyP, an ancient molecule that may have preceded ATP as the
primary energy source driving prebiotic reactions, has been retained by
evolution and is still utilised in many modern cellular processes.
The laboratory is collegial and very cooperative. We
are always open to new collaborations aimed at elucidating the multifaceted
aspects of inositol pyrophosphate and inorganic polyphosphate signalling.