Bulletin

Issue: September/October 2007

News

New trigger for cell death

An Australian-based multi-national research team led by La Trobe University research scientist Dr Hamsa Puthalakath has identified a key mechanism responsible for triggering the self-destruction of human cells.

Dr Puthalakath and his colleagues from The Walter and Eliza Hall Institute have discovered that a protein named BIM is a critical player in the process of cell suicide known as ‘apoptosis’.

A member of a family of proteins (Bcl- 2) whose principal function is to trigger the death of unwanted or damaged cells, BIM is now revealed as the major player in the death of cells from stress.

The team’s findings were published in a recent issue of the prestigious journal Cell. Dr Puthalakath’s team has spent five years investigating what happens when the cell’s normal protein-processing system goes awry, jamming proteins that should be exported to other parts of the cell or beyond, in the folds of its endoplasmic reticulum (ER).

He explains it is the ER’s function to package, ‘fold’ and store newly manufactured proteins before relocating them to other parts of the cell for further modification, before they are secreted from the cell. In the process of being
‘folded’, which is essential for their correct functioning, some proteins become jammed, causing cellular stress.

In response to this blockage the cell first tries to fix itself. If this fails, it then ‘pulls the trigger’, activating an in-built self-destruct mechanism, to die by apoptosis.

Dr Puthalakath and his fellow researchers have identified BIM as the trigger for ER stress-induced apoptosis.

The research group includes Professor Andreas Strasser and Drs Lorraine O’Reilly, Priscilla Gunn, Lily Lee, Priscilla Kelly, Nick Huntington, Ewa Michalak, and Philippe Bouillet from WEHI, CSIRO scientist Dr Jennifer McKimm-Breschkin, and Japanese scientists Dr Noburo Motoyama (from the National Institute for Longevity Sciences, National Centre for Geriatrics and Gerontology, Aichi, Japan), and Dr Tomomi Gotoh (from Kumamoto University, Kumamoto, Japan.)

Dr Puthalakath says when the ER is stressed, BIM was found to translocate and then bind itself to its siblings, antiapoptotic proteins such as Bcl-2, first identified as a regulator of apoptosis by La Trobe’s new ‘Australia Fellow’, Professor David Vaux, see story page 3.

Apoptosis is a normal process needed for development in the womb, and to remove damaged, dangerous and surplus cells later in life. (The word apoptosis derives from a Greek word meaning
‘falling off’, as in ‘leaves of a tree.’) It is essential for the development and functioning of all multi-cellular animals including humans. More than 90 per cent of the neurons produced in a normal foetus, ie, those that are not connected properly, are fated to die before a baby is born. If cells between our fingers didn’t die during embryonic development, for instance, we would be born with webbed hands.

In maturity, apoptosis maintains the proper number of cells by balancing cell production. Apoptosis is also critical as a defence against disease. Cells dying prematurely can lead to neuro-degenerative diseases; conversely, the failure of cells to die when they should can give rise to autoimmune disease and tumours.

Dr Puthalakath explains what happens:
‘ER stress can be provoked by a variety of patho-physiological conditions including ischaemia and viral infection, as well as mutations that impair the proteinfolding function in cells. This response can involve activation of repair processes, so that the cell survives, by reducing the load of unfolded proteins in the cell – but when ER stress is overwhelming, the cells undergo apoptosis.

‘Our new study has defined the molecular mechanisms of ER - stressinduced apoptosis. This is important because abnormal ER stress and consequent premature apoptosis has been implicated in a range of diseases.’ The research team found specifically that ER stress induced by cytotoxic drugs or mis-folded proteins activated the gene for BI M, and increased BI M protein levels in diverse cell types, which triggered apoptosis.

‘People in the field have thought that other proteins, such as caspase 12, were directly responsible, but we’ve now shown clearly and unequivocally that the protein involved in many tissue types such as kidney epithelial cells, macrophages and thymocytes, is BIM,’ Dr Puthalakath says.

He and his colleagues hope their work will lead to the design of new drugs and therapies.

‘The results may assist in developing improved therapies for many ER-related disease including cystic fibrosis, cirrhosis of the liver, and type 2 diabetes,’ he says. Dr Puthalakath and his team aim to continue their research into the link between ER stress-induced apoptosis and human immune response, to see if the same mechanisms are used by the immune system when it destroys potentially self-reactive lymphocytes that could otherwise cause autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus.

Their work is closely integrated at La Trobe with other major studies by Professor Vaux, whose pioneering work on the molecular mechanisms of apoptosis in the 1980s helped establish the field of cell death research. In the last 12 months, more than 15,000 scientific publications have mentioned apoptosis. Since moving to La Trobe in 2006, Professor Vaux has worked closely with Professor Nick Hoogenraad, Head of the School of Molecular Sciences, building a critical mass of scientists providing world-class research in this highly competitive field.