Gasdermin and the illusive inflammasome
By Hugh Shirley, Biochemistry, 2019
This piece was originally published as part of Issue 40: Wonder.
There’s more than one way that a cell can kill itself. The standard version of cell suicide, apoptosis, is happening constantly within our bodies. When a cell detects damage, harmful mutations, or infection, apoptosis is often the response. This process has evolved to be clean, quiet, and effective, so that surrounding cells are not damaged while the immune system cleans up the apoptotic cell’s debris. Apoptosis refers to programmed cell suicide and has been at the center of countless cancer, aging, and development studies, but cells can undergo more than just apoptosis in response to damage. Enter pyroptosis and the Gasdermin protein family.
Pyroptosis was coined in 2001 from the Greek “pyro” for fire and “ptosis” for falling. Inflammation caused by bacterial infections has been studied as part of natural immune response for centuries. In 2001, Dr. Brad Cookson first described pyroptosis as a cellular mechanism behind that response. For over a decade, it was not well understood how pyroptosis occurred in cells. It was known that infected immune cells, such as macrophages, would develop relatively large pores in their membrane, flooding the extracellular environment with the components of their cytoplasm, like a deflating balloon. The crucial piece of missing information was how the large pores in the membrane were made in the first place. Many of the early papers on pyroptosis left a big question mark for that part of the pathway.
Inflammation caused by bacterial infections has been studied as part of natural immune response for centuries.
The pyroptotic pathway involves the formation of a protein complex called the inflammasome. The aptly named assembly is built in response to signals from intracellular bacteria, viruses, or cell damage. One goal of the inflammasome is to activate caspase-1. Caspase-1 is the protein that was long thought to be the cause of the membrane pores associated with pyroptosis, but a recent paper revealed that that wasn’t the case. Gasdermin, a family of proteins linked with pyroptosis, was discovered as the actual pore forming protein in 2017 by Dr. Ana Morandini. Caspase-1 is responsible only for cleaving away parts of the inactive gasdermin protein, allowing the active portion to carry out its pyroptotic mission. Caspase-1 also activates interleukin-1β. Active IL-1β can flood through the holes created by gasdermin into the extracellular environment and help stimulate further inflammation by recruiting more immune system cells to the area.
Gasdermin has a lot of potential as an antibiotic. The ability to punch holes into membranes is a highly coveted biological advantage that many organisms exploit through multiple strategies. Studies have shown that active gasdermin spontaneously forms pores in lipid bilayers in solution — meaning that once caspase-1 cleaves gasdermin into its active form, there’s nothing stopping its pyroptotic activity. One remaining question is how gasdermin gets through a prokaryotic outer peptidoglycan wall so that it can access the membrane. While the pharmaceutical applications are still a big unknown for gasdermin, we do know more than previously about what’s happening in vivo during pyroptosis and why it occurs in the first place.
Pyroptosis, while at first glance might seem like a big negative for host cells, can provide several immunological advantages.
Pyroptosis, while at first glance might seem like a big negative for host cells, can provide several immunological advantages. By flooding the extracellular environment with toxic metabolic compounds from the pyroptotic cell, the body can fight off bacteria that’s growing in that extracellular space. The recruitment of additional immune system cells to the area through the release of signal molecules like IL-1β further strengthens the body’s fight against pathogens. Pyroptosis, and therefore gasdermin, can still cause significant damage to the host. Uncontrolled pyroptosis is linked with septic shock. Septic shock is a life threatening stage of sepsis, or infection of the blood. Inflammation and sepsis go hand in hand, so pyroptotic cells that release inflammation inducing signaling molecules in response to a bacterial infection could be the reason behind septic shock.
The relatively new molecular world of pyroptosis is an ongoing field of study. Gasdermin provides the missing link between what induces pyroptosis and the physiological signs that we observe. Now, with a more complete picture, researchers can study how we can take advantage of gasdermin as an antibiotic and as a player in septic shock. Who knew there was so much more to cell suicide!
Biomedical Journal (2017) DOI: 10.1016/j.bj.2017.10.002
Trends in Biochemical Sciences (2017) DOI: 10.1016/j.tibs.2016.10.004
Trends in Microbiology (2001) DOI:10.1016/S0966–842X(00)01936–3