Protein homeostasis is essential to the physiological function and viability of eukaryotic cells; particularly neurons, where proteome integrity must be maintained for decades. Protein synthesis is energetically demanding, but all proteins accrue damage and must be replaced. Protein turnover thus consumes a large proportion of cellular energy budgets. The assembly of macromolecular complexes is especially challenging since supernumerary/misfolded subunits can aggregate/gain deleterious functions. Healthy cells prevent proteome imbalance by synthesizing and degrading MMC subunits stoichiometrically, through temporal co-ordination of the translational/degradation machineries. This temporal consolidation of proteome renewal is principally regulated by mechanistic target of rapamycin complex 1 (mTORC1). Transitions between high and low mTORC1 activity states occur with a daily rhythm across a range of animal, plant/algal and fungal cells. The mechanisms and temporal regulation of these state transitions are incompletely understood but involve profound re-organisation of cellular composition through dynamic changes in protein phosphorylation, ion transport, macromolecular crowding, metabolic flux, biomolecular condensation and trafficking.
Working within an inclusive multi-disciplinary team, your research will build on our previous work to delineate the consequences, temporal regulation and biochemical mechanisms of daily transitions in cellular state. Techniques will include culture of cell lines and stem-cell derived neurons, bioluminescence imaging, live cell microscopy, quantitative mass spectrometry, transgenic complementation, genome editing, electrophysiology, behavioural assays, and opto-/chemigenetics. You will use these tools and methods to characterise state transitions during the cellular circadian cycle, with a focus on neuronal cell biology and relevance to sleep/wake changes in the brain.
The successful applicant will have a degree in biochemistry, cell biology or a related area. You should be enthusiastic and creative with good communication, organisational and numeracy skills. Previous experience with tissue culture and programming would be desirable.
If you share our interest in biological timing and would like to work with us, please get in touch to find out more.
References
Feeney et al., (2016) Daily magnesium fluxes regulate cellular timekeeping and energy balance. Nature. 532,375–379
O'Neill et al., (2020) Eukaryotic cell biology is temporally coordinated to support the energetic demands of protein homeostasis. Nature Comms,11, Article number: 4706
Stangherlin et al., (2021) Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology Nat Comms. 12, Article number: 6035
Stangherlin et al., (2021) Understanding circadian regulation of mammalian cell function, protein homeostasis, and metabolism Curr Opin Sys Bio.