Cell Suicide: Caspases Call the Shots

| Written by Susan Gammon
acute necrosis (cell death) of the liver cells

People are usually surprised to learn that many cells in our bodies essentially commit suicide. These cells don’t die because they are sick, but because they are following built-in signals that initiate their death. 

A few examples illustrate how this regulated cell death is really not surprising at all, but in fact is essential for proper development and health: 

  •  Developing fetuses generate many more cells than they can use. Excess cells that don’t contribute effectively to developing tissues must be eliminated to avoid accumulation of non-functional cells. 
  •  Many adult tissues contain cells that proliferate rapidly to replace old, worn-out cells. Without elimination of the old cells, tissues would balloon up  with non-functional cells. Adults may lose more than 50 billion cells every day due to this cell replacement process. 
  • Abnormal cells need to be eliminated to avoid development of diseases like cancer. The loss of ability to undergo regulated cell death is one  hallmark of malignant cancer cells.

What really is surprising about regulated cell death is the number of different ways cells can terminate themselves. This suggests that the different cell death pathways must communicate with each other to decide which mechanism will be used in a given situation. 

In a commentary in Cell Chemical Biology, Guy Salvesen, Ph.D., professor at  SBP reviews a recent report that partly solves the riddle of communication between two of these cell death pathways, called apoptosis and pyroptosis. 

Salvesen explains, “Apoptosis and pyroptosis are similar in that they both rely on protein-cleaving enzymes called caspases to carry out the cell death sentence. But there are big differences. Pyroptosis is a messy death that releases a lot of cell debris, activates the immune system and triggers inflammation. It does this via caspase-1, a version of the enzyme that chops up a protein called gasdermin-D (GSDMD) to create a small toxic piece of GSMD that mediates the process.  

“In contrast, apoptosis uses caspase-3 and caspase-7 to initiate cell death by damaging the cell nucleus and its DNA, causing a relative quiet cell death with minimal disruption to the rest of the body. These caspases also cleave GSDMD, but in way that doesn’t create the toxic fragment. Apoptosis is dominant—so once it’s triggered pyroptosis is put on the back burner.”

First author Marcin Poreba, Ph.D., a postdoc in the Salvesen lab, adds that, “The decision of a cell to use pyroptosis versus apoptosis depends to a large extent on the strength of the death signals the cell receives. In most cases, apoptosis will win out because of its ability to block the pyroptosis process. This is a good thing, since regulated cell death usually occurs as part of normal development and maintenance programs in which inflammation should be avoided. But in cases where pyroptotic stimuli are strong enough, for example in response to the need to eliminate cells infected by bacteria or viruses, the pyroptotic pathway can override apoptosis and terminate cells in a way that also recruits the immune system into the battle. It’s almost like a contest to see which caspases win the death race. 

Read the paper here.

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