In the human body there is a constant balance between cell growth and cell death. Cells that are old or diseased must be eliminated. The destruction of diseased cells plays a major role especially in infectious diseases, chronic inflammatory diseases, and cancer.
Signals coming from death receptors located on the cell surface tell the cells whether they can continue to live and divide, or if they must take the path of destruction. The orderly path is apoptosis, in which the cell dismantles itself into its individual components and is taken up by phagocytes. But there is another path to cell destruction. It is regulated by distinct signals, and is called necroptosis. It starts via the same signals as apoptosis, but then the cells commence self-digestion. As in pathological necrosis, the cell components make their way into the extracellular space, causing an inflammatory reaction in the surrounding tissue.
The TNF (tumour necrosis factor) receptor 1 is one of the most important death receptors. Luigi Tortola and Roberto Nitsch, co-first authors of a current publication in Cell Reports, discovered that “the enzyme HACE1 is the key regulator of the TNF receptor 1. If HACE1 binds to the receptor, either the “life signal” or the signal of controlled destruction, apoptosis, is transmitted. But if HACE1 is missing, there is no more survival or apoptosis; the only option left for the cell is necroptosis.”
The consequences can be seen in the current study, in which mice that lack the HACE1 enzyme are significantly more vulnerable to intestinal inflammation, and develop bowel cancer far more often due to constant inflammation. Josef Penninger, scientific director at IMBA and last author of the publication, was surprised at the findings: “Many years ago I was in Canada when the tumour-suppressing effect of HACE1 was discovered. No one knew then how this mechanism worked. Now we have found that this effect comes about when HACE1 intervenes directly in cell fate and determines whether the cell with live or die, and especially how it will die. That is an utterly new discovery.”
The study also showed that the intestinal inflammation proven in mice and the frequent occurrence of bowel cancer can be improved significantly through genetic blockade of the death receptor. The scientists want to use this finding for further research.
Tortola, L., Nitsch, R. et. al. (2016). The tumor suppressor Hace1 is a critical regulator of TNFR1-mediated cell fate. Cell Reports.