Project

Unraveling IRE1 endonuclease activity and its role in regulating cell fate: an interactomics approach.

Code
3E010513
Duration
01 October 2013 → 30 June 2014
Funding
Regional and community funding: Special Research Fund, Research Foundation - Flanders (FWO)
Research disciplines
  • Medical and health sciences
    • Laboratory medicine
    • Palliative care and end-of-life care
    • Regenerative medicine
    • Other basic sciences
    • Laboratory medicine
    • Palliative care and end-of-life care
    • Regenerative medicine
    • Other clinical sciences
    • Other health sciences
    • Nursing
    • Other paramedical sciences
    • Laboratory medicine
    • Palliative care and end-of-life care
    • Regenerative medicine
    • Other translational sciences
    • Other medical and health sciences
Keywords
role in regulating cell fate interactomics approach endonuclease activity IRE1
 
Project description

The Inositol Requiring Enzyme 1 α (IRE1α) is one of the key mediators of the unfolded protein response, an evolutionary conserved homeostatic response aimed at balancing endoplasmic reticulum (ER) protein synthesis and protein folding capacities to the needs of the cell. IRE1α, via the endonuclease activity in its cytoplasmic tail, plays essential roles in physiology as a regulator of the secretory pathway. Accumulating evidence moreover indicates IRE1α is implicated in a variety of illnesses, including diabetes, inflammatory diseases and cancer. Interestingly, IRE1α appears to be a highly versatile protein, whose action involves the recruitment of numerous partner proteins thereby constituting a novel protein scaffold at the ER. Several findings moreover suggest that the composition of the IRE1α complex modulates its endonuclease activity, determining cell fate decisions. An in-depth understanding of contextspecific IRE1α function is however lacking at the moment. In this project, we propose a strategy, combining different genome-wide protein-protein interactions analysis methods, to create a high-confidence map of the dynamic IRE1α interactome. The impact of selected interactions on IRE1α endonuclease activity and cell fate will be validated in functional in vitro assays. The aim of this project is to reveal novel IRE1α interactions that, by modulating IRE1α endonuclease activity, determine cell fate in cells subjected to ER stress and hence could be therapeutic targets.