Discovery of mechanism for killing cells that are stressed

A part of every cell is a network of folds called the endoplasmic reticulum (ER), which operates as a packaging and storage system for proteins to be translocated to different parts of the cell.

Sometimes the normal processes for the production and export of proteins go awry and proteins become jammed in the folds of the ER. When this happens, the cell experiences stress, which can activate its intrinsic self-destruction program, known as apoptosis.

Apoptosis is a normal and healthy process that the body uses to dispose of old, damaged, dangerous or surplus cells. About a million cells undergo apoptosis in the human body every second. The cells that are destroyed are replaced by the same number of new and healthy cells.

The problem with proteins becoming jammed in the folds of the ER is that the consequent cellular stress (Unfolded Protein Response or UPR) can induce the premature death of cells that should normally survive.

Using mouse models, Dr Hamsa Puthalakath and Professor Andreas Strasser and their colleagues have discovered that activation of the pro-apoptotic regulator Bim is responsible for inducing cell death induced by ER stress.

Understanding the mechanisms of premature cell death caused by ER stress is important because abnormal ER stress and consequent premature apoptosis have been implicated in the development of a range of diseases, including cystic fibrosis, pancreatitis and type 2 diabetes. The results from this study are expected to assist the development of improved therapies for these diseases.

The research team led by Hamsa Puthalakath and Andreas Strasser comprised Lorraine O’Reilly, Priscilla Gunn, Lily Lee, Priscilla Kelly, Nick Huntington, Peter Hughes, Ewa Michalak, Jennifer McKimm-Breschkin, Noburo Motoyama, Tomomi Gotoh, Shizuo Akira, and Philippe Bouillet.