My laboratory is investigating how cells die via a process called apoptosis.
Apoptotic cell death is a normal process that helps remove excess or damaged cells. When apoptotic cell death goes wrong, the results are often cancer or autoimmune diseases.
My laboratory is interested in the proteins inside cells that orchestrate apoptosis. We are focusing on how the killer proteins, BAX and BAK, cause organelles called mitochondria to be leaky and kill the cell. Understanding this process is critical to developing new treatments that either enhance or block apoptosis in cancer and autoimmune disease.
A key event in apoptotic cell death is the oligomerisation of the BAX and BAK proteins to form pores in mitochondria, although how they form pores is still unclear.
We recently found that cells lacking the putative trafficking protein PACS1 are resistant to apoptosis due to unusual complexes of BAX and BAK (Brasacchio et al, Cell Death Differ, 2017).
We are thus characterising the unusual BAX and BAK complexes in PACS1-knockdown cells to understand this new means of resistance.
As the formation of BAX and BAK homo-oligomers strongly correlates with their ability to perforate mitochondria, defining how BAX and BAK dimers self-associate and interact with the membrane will reveal how they trigger apoptosis.
Our data indicate that dimers do not interact by distinct protein-protein interface, but form disordered clusters to generate pores (Uren et al, eLife, 2017; Uren et al, Philos Trans R Soc Lond B Biol Sci, 2017).
A range of biochemical approaches will examine further how the outer membrane is involved in oligomerisation of dimers.
Inhibition of apoptosis by prosurvival BCL-2 proteins contributes to oncogenesis and to resistance to cancer treatments. In particular, MCL-1 can cause resistance by sequestering activated BAK.
We aim to better understand when and how MCL-1 and BAK interact in different cancer cells following treatment, and so identify ways of circumventing this resistance.
We found that an antibody to the BAK protein can trigger its activation leading to mitochondrial pore formation and cell death (Iyer et al, Nat Commun 2016 7:11734).
To investigate if this antibody can be developed as a novel anti-cancer agent, this project will combine the anti-BAK antibody with others that can be taken up by cancer cells, and test for induction of cell death.
My lab collaborates closely with the Structural Biology division and other divisions in the Institute and elsewhere who study the protein interactions that regulate apoptosis in health and disease.