Understanding why two of the enzymes involved in the regulation of rate limiting steps of
triacylglycerol (TAG) and phospholipid (PL) synthesis typically localise to the nucleus.
Dr David Savage (Institute of Metabolic Science) and Dr Symeon Siniossoglou (CIMR)
The two labs have worked on related projects in collaboration for the past 18 months or so,
and would benefit greatly from the added impetus of a talented PhD student.
Lipids play three essential roles in biology: firstly, cells use lipids as building blocks for the
formation of membranes and organelles. Secondly, lipids produce chemical messages by
which organelles communicate with each other. Thirdly, neutral lipids known as
triglycerides, or fat, represent the major form by which cells store energy and can be
mobilized at a time of need. Disrupting the balance of stored versus mobilized fat can cause
serious metabolic disorders and is at the heart of the current diabetes pandemic.
Lipid biosynthesis is mediated by the co-ordinated action of
enzymes that concentrate mostly on the cytoplasmic
membranes of cells. The core reactions of lipid biosynthesis
are conserved from unicellular eukaryotes to humans. This
allows us to use simple model systems to dissect the complex
lipid biosynthetic pathways. Dr Siniossoglou’s research focuses
on Pah1 which catalyses a universally conserved metabolic
reaction that controls both the formation of new membrane
phospholipids for cell growth and triglyceride for energy
storage. His group has previously found that in addition to the
cytoplasmic membrane-associated Pah1, cells have also
another pool of Pah1 in the nucleus whose function is, so far,
unknown.
Dr Savage’s laboratory has recently identified loss-of-function mutations in PCYT1A in people
with severe metabolic disease. PCYT1A is an enzyme responsible for the rate-limiting
reaction in the Kennedy phosphatidylcholine (PC) biosynthesis pathway. PC is the major
phospholipid component in all cell membranes and so is essential in all living cells.
Surprisingly, like Pah1, PCYT1A is also localised to the nucleus in the ‘basal’ state but then
moves to the surface of expanding membranes, where it senses the need for more PC and is
activated in these conditions. Interestingly, the product of Pah1 is also used by the Kennedy
pathway and PCYT1A for membrane biogenesis but whether the activities of the two
enzymes are coordinated remains unknown.
Pah1 and PCYT1A are found in the nuclei of both yeast and human cells suggesting that their
nuclear functions have been conserved over millions of years of evolution. The aim of this
project is to investigate the nuclear roles of these enzymes by examining their functions in
nuclear membrane biogenesis, gene expression or nuclear lipid signalling. The project will
make use of novel mutants of Pah1 and PCYT1A, defective in nucleocytoplasmic trafficking,
and explore the mechanism of their nuclear translocation using state of the art live cell
imaging, lipidomic, biochemical and gene expression approaches both in yeast and
mammalian cells.