Australasian Science: Australia's authority on science since 1938

New Use for Death Protein

By Stephen Luntz

The involvement of a protein in the body’s back-up mechanism for cell death makes it a target for drugs against a wide variety of diseases.

Cell death normally occurs through apoptosis, a process where the cells self-destruct when they represent a threat to the body. However, since apoptosis will kill bacteria or viruses that have infected the cells, evolution has encouraged some infectious agents to find ways to avoid it.

As part of the ceaseless arms race with disease, animal cells have a back-up plan known as necroptosis. “During necroptosis, the cell still self-destructs but in doing so it also sends an ‘SOS’ to the immune system to tell it that something has gone wrong with the cell’s normal cell death process of apoptosis,” says A/Prof John Silke of the Walter and Eliza Hall Institute. All cells in the body have the potential to use necroptosis if necessary.

Sometimes necroptosis occurs when it should not, triggering inflammatory diseases such as Crohn’s and rheumatoid arthritis. According to

Dr James Murphy of WEHI: “It is not really clear how this happens, but I am happy to speculate. The best guess is that the cells send a signal to the immune system that indicates necroptosis, leading to an immune response even when there is no infection.”

Murphy and Silke are among the authors of a paper in Immunity revealing the role that the MLKL protein plays in this signalling. “Necroptosis has only been defined in the past 10 years, and the role MLKL plays was only discovered in 2012,” Murphy says. “This study provides the first genetic proof that MLKL is required for necroptosis as well as the first full-length, atomic level, three-dimensional structure of a protein that regulates necroptosis.”

In the long run a mechanism for triggering necroptosis could be a way to fight cancers, but Murphy says: “Our drug discovery is focused on inhibitors first, because it is easier to find something that blocks than enhances”. If successful, the drug could offer relief to sufferers of a wide variety of inflammatory diseases.

The images of MLKL’s structure reveal it to be a pseudokinase, a class of enzymes that Murphy says were once thought to be “part of the cell’s detritus”. Pseudokinases are now known to have important roles provided other enzymes can trigger them.