Developing mathematical models for the induction of programmed cell death by ER stress in Arabidopsis thaliana

  • Jia Yu

Student thesis: Phd

Abstract

Endoplasmic Reticulum (ER) is a vital part for functional protein synthesis in eukaryotic cells. ER stress is caused by over-accumulation of unfolded or misfolded proteins, which are massively produced in dysfunctional protein synthesis in the ER lumen. In a plant cell, ER stress can be induced by various environment factors, such as saline stress and heat stress. Under ER stress, a self-defensive mechanism, unfolded protein response (UPR), can be activated to restore the homeostasis from ER stress in a systemic way. Unlike the UPR in mammalian cells, by now only two pathways have been identified: IRE1α/β pathway and bZIP28 pathway. Both IRE1α/β and bZIP28 are ER stress sensors located on the ER membrane. IRE1α/β is activated under sensing the accumulation of unfolded protein in the ER lumen and then catalyse the splicing of bzip60 mRNA. Spliced bzip60 mRNA will finally be translated to transcription factor bZIP60 . bZIP28, when activated by sensing unfolded proteins in the ER lumen, will dissociate from the ER membrane and then be further cleaved by protease at Golgi before turning to transcription factor bZIP28. The transcription factor bZIP60 and bZIP28 can then promote the transcription of a group of UPR genes. A gene of molecular chaperone, BiP, is one of the typical UPR genes and BiP protein can help alleviate ER stress by refolding the badly folded proteins in the ER lumen. In recent researches, ER stress was found to be connected with plant pro- grammed cell death (PCD). Under prolonged ER stress, plant cells would finally go to PCD and caspase-like activity before cell death can be detected by exper- imental techniques. Additionally, more evidence was presented to link ER stress and plant PCD. One important transcription factor, NAC089, was found not only to be involved in UPR signalling (controlled by both bZIP60 and bZIP28), but could also promote PCD in plant cells. The conflicting roles of NAC089 play could potentially decide the fates of cells under ER stress. In this thesis, we are going to use both experimental and computational meth- ods to further understand the UPR in plant cells based on the current knowledge. We first present the functions of cathepsin-B and proteasome under ER stress, giving more evidence of the connection between ER stress and plant PCD. Next, we hope to know more about the role that NAC089 plays under ER stress. We present a novel mathematical model on the UPR signalling, with NAC089 included. We present both algebraic and numerical analysis of the model we use. In this model, we use ordinary differential equations (ODEs) in order to make prediction of cell-fate decision in a quantitative way. To have an insight of the fate decision under ER stress in Arabidopsis, we present our data using different experimental systems, from single cell protoplast system to plant leaf tissue system. We also introduce our design of an original ‘Time-Dose’ matrix approach for Arabidopsis seedling system in the thesis. Our matrix approach shows clear phenotype difference in seedlings under different ER stress conditions. Finally, we try to use our UPR model to compare the transcript changes with our experimental data. We find our UPR model still needs improve- ment due to some incompatibilities between the experimental data and our UPR model, although the model makes some promising predictions at the same time.
Date of Award31 Dec 2019
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorGiles Johnson (Supervisor), Patrick Gallois (Supervisor) & Oliver Jensen (Supervisor)

Keywords

  • ER stress
  • Unfolded Protein Response
  • stress response
  • modelling cell signalling
  • Arabidopsis

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