Researchers have uncovered how human cells get ‘triggered’ to undergo an inflammatory type of cell death called necroptosis, a finding that could facilitate new treatments for cancer, immune disorders, stroke and tissue injury. The research was done by scientists at the Walter and Eliza Hall Institute and published today in Nature Communications.
Excessive necroptosis has been linked to a number of diseases including stroke and organ transplant injury and necroptosis abnormalities have been linked to cancer.
In the current study, a cancer scenario was ‘reconstructed’ in human cells with MLKL mutations like those found in some human cancers. This led to the discovery that most mutations in MLKL in human cancers lead to delayed cell death by necroptosis.
"One of the curious things about this protein [MLKL] is that it is found in all cells of the body all the time, just sitting there waiting to kill the cell and alert the immune system to a problem,” said Dr. Emma Petrie, one of the study’s lead authors. This led the team to conclude that there must be tight control over the process to avoid harmful consequences.
According to the authors, this is the first time MLKL protein’s mechanism has been visualized in human cells and the action was shown to differ from the mouse model systems currently available. They were also able to resolve what the dormant and active forms of MLKL look like and how its partner protein RIPK3 binds to MLKL to trigger inflammatory cell death.