Exploring accessible nodes in the unfolded protein response


  • Prof David Ron

    University of Cambridge

Project summary

Proteins are comprised of linear chains of different amino acids, the order of which is specified by the genome. Functionality of these key building blocks of life requires that the protein chain fold onto itself to create a three-dimensional object. Misfolded proteins may be toxic to cells. The accumulative burden of generating properly folded proteins from newly-synthesised unfolded ones is believed to contribute to ageing and disease. This is especially conspicuous in the endoplasmic reticulum (ER), a small compartment in which proteins that are destined to function outside cells are folded and processed. Cells are endowed with an apparatus for coping with the burden of unfolded proteins in their ER, but the implementation of this unfolded protein response (UPR) entails important trade-offs. This system, which developed over a billion years, is not optimised for longevity and its edges expose failures of homeostasis.

We aim to uncover nodes in this regulatory network that can be weakened or augmented to therapeutic ends. This involves discovering specific components of the UPR that can be tweaked with chemicals.

It is hoped that we can optimise the system for the needs of people and animals with a longer life span.