Investigating the consequences of asymmetric endoplasmic reticulum inheritance in Saccharomyces cerevisiae under stress using a combination of single cell measurements and mathematical modelling

Felix R.H Jonas,Kate E Royle,Rochelle Aw,Guy-Bart V Stan,Karen M Polizzi

doi:10.1016/j.synbio.2018.01.001

Felix R.H Jonas, Kate E Royle + Show 3 more

Open Access

https://doi.org/10.1016/j.synbio.2018.01.001

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Abstract

Adaptation allows organisms to maintain a constant internal environment, which is optimised for growth. The unfolded protein response (UPR) is an example of a feedback loop that maintains endoplasmic reticulum (ER) homeostasis, and is characteristic of how adaptation is often mediated by transcriptional networks. The more recent discovery of asymmetric division in maintaining ER homeostasis, however, is an example of how alternative non-transcriptional pathways can exist, but are overlooked by gold standard transcriptomic or proteomic population-based assays. In this study, we have used a combination of fluorescent reporters, flow cytometry and mathematical modelling to explore the relative roles of asymmetric cell division and the UPR in maintaining ER homeostasis. Under low ER stress, asymmetric division leaves daughter cells with an ER deficiency, necessitating activation of the UPR and prolonged cell cycle during which they can recover ER functionality before growth. Mathematical analysis of and simulation results from our mathematical model reinforce the experimental observations that low ER stress primarily impacts the growth rate of the daughter cells. These results demonstrate the interplay between homeostatic pathways and the importance of exploring sub-population dynamics to understand population adaptation to quantitatively different stresses.

Highlights

Adaptation is the basic mechanism that enables organisms to thrive in a changing, and often challenging, environment
unfolded protein response (UPR) is not necessary for survival during low endoplasmic reticulum (ER) stress, but both UPR and ER surveillance (ERSU) contribute to adaptation
While wild-type yeast cells could grow at all concentrations of tunicamycin, growth of the Dhac1 cells was only detected at 100 ng/mL. This both highlights the importance of UPR activity in adaptation to ER stress, but reveals redundancy in ER

Summary

Introduction

Adaptation is the basic mechanism that enables organisms to thrive in a changing, and often challenging, environment. Both single and multicellular organisms have evolved a set of internal conditions that allow them to fully exploit an ecological niche. Organisms maintain this homeostasis by adapting: different stresses are detected by specific sensors, which trigger bespoke transcriptional responses [1]. This regulation of gene networks collectively acts to reinstate homeostasis, be it through an. The ER, a large organelle comprising a single lipid bilayer and enclosed lumen, extends as a network throughout cell and is responsible for a diverse range of functionalities including: (i) protein synthesis, folding and quality control, (ii) calcium storage and (iii) lipid metabolism [5e7]

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