Under control until the end: how our cells kill themselves

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Cell death is crucial for all organisms. Damaged cells or cells infected with viruses or bacteria kill themselves by starting a built-in “suicide” program, which prevents the development of tumors and the spread of pathogens in the body.

Until recently, it was assumed that cells simply burst and die at the end of their lives. Now, researchers from the Biozentrum of the University of Basel, the University of Lausanne and the Department of Biosystems Science and Engineering (D-BSSE) at ETH Zurich have provided new insights into the final step of cell death. In the scientific journal “Nature”, they describe how a protein called ninjurin-1 assembles into filaments that work like a zipper and open the cell membrane, leading to the disintegration of the cell. The new insights are an important milestone in understanding cell death.

The protein acts as a breakpoint in the cell membrane.

Various signals, such as bacterial components, activate the cell death machinery. In the final stage of this process, the cell’s protective membrane is compromised by tiny pores that allow ions to enter the cell. “The common understanding was that the cell then swells until it finally bursts due to increased osmotic pressure,” explains Professor Sebastian Hiller, who leads a research group at the Biozentrum of the University of Basel. “We are now resolving how cells actually rupture. Instead of bursting like a balloon, the ninjurin-1 protein provides a breakpoint in the cell membrane, causing rupture at specific sites.”

Using advanced techniques such as highly sensitive microscopes and NMR spectroscopy, scientists have been able to elucidate the mechanism by which ninjurin-1 induces membrane rupture at the level of individual atoms. Ninjurin-1 is a small protein embedded in the cell membrane.

“Upon receiving the suicide command, two ninjurin-1 proteins initially clump together and drive a wedge into the membrane,” explains Morris Degen, first author of the study and a doctoral student at the Swiss Institute of Nanoscience’s Doctoral School. “Large lesions and holes are formed by many additional proteins that bind to the initial wedge. In this way, the cell membrane is opened piece by piece until the cell completely disintegrates.” Cell debris is then removed by the body’s own cleansing service.

“It is now clear that cells do not burst without ninjurin-1. They swell to some degree due to ion ingress, but membrane rupture depends on the function of this protein,” adds Hiller. “The textbook chapter on cell death will be expanded with these beautiful structural insights.”

Therapy to prevent or promote cell death

A deeper understanding of cell death will facilitate the search for new drug targets. Therapeutic interventions to treat cancer are conceivable, since some tumor cells evade programmed cell death. Furthermore, in the case of premature cell death seen in neurodegenerative diseases such as Parkinson’s disease or life-threatening conditions such as septic shock, drugs that interfere with this process are a potential treatment option.