Programmed cell death is a biological process that maintains tissue health and protects the body from threats like infections and abnormal cell growth. It is a highly regulated mechanism, distinct from accidental cell death, ensuring that damaged or unwanted cells are removed efficiently. Within this process, a protein known as Gasdermin D plays a role in a specific type of inflammatory cell death. Understanding this molecule helps reveal how the body defends itself and how certain diseases develop.
What is Gasdermin D?
Gasdermin D is a protein belonging to the gasdermin family, a group of six related proteins in humans, including Gasdermins A, B, C, D, E, and Pejvakin (DFNB59). While all gasdermins share structural similarities, Gasdermin D has been studied for its role in a distinct form of cell death. It was identified as a player in pyroptosis in 2015, clarifying the mechanisms behind this inflammatory process.
The full-length Gasdermin D protein is composed of two main sections: an N-terminal domain (p30) and a C-terminal domain (p20). These two parts are connected by a flexible linker region, which is important for its function. In its inactive state, the C-terminal domain binds to and inhibits the N-terminal domain, preventing it from causing cell damage.
How Gasdermin D Works
The activation of Gasdermin D begins with its cleavage by specific inflammatory enzymes known as caspases. Caspases involved include caspase-1, caspase-4, caspase-5, and caspase-11, which are activated within multi-protein complexes called inflammasomes. These caspases target a specific tetrapeptide sequence within the flexible linker region of Gasdermin D.
Once cleaved, the N-terminal domain of Gasdermin D is released from its inhibitory C-terminal counterpart. This liberated N-terminal fragment then moves to the cell’s outer membrane, the plasma membrane. There, multiple N-terminal fragments come together, or oligomerize, to form large, circular pores. These pores vary in size and are composed of multiple subunits.
The formation of these pores in the cell membrane disrupts the cell’s integrity. This creates openings that allow substances to pass through, leading to changes within the cell. This pore-forming activity is the direct mechanism by which Gasdermin D executes its cellular function, without yet leading to the full cell death process.
Its Role in Pyroptosis
Gasdermin D serves as the executioner of pyroptosis, a distinct and inflammatory form of programmed cell death. Unlike apoptosis, which involves cell shrinkage and dismantling without causing inflammation, pyroptosis is characterized by cell swelling, the formation of membrane pores by Gasdermin D, and ultimately, cell lysis. This rupture of the cell membrane allows the release of various intracellular contents, including pro-inflammatory molecules.
The release of these components, such as interleukin-1 beta (IL-1β) and interleukin-18 (IL-18), acts as alarm signals to the immune system. This distinguishes pyroptosis from apoptosis, which is considered non-inflammatory. Gasdermin D’s pore-forming activity drives this inflammatory cell death pathway, making it a mediator in the body’s immune responses to various threats.
Pyroptosis plays a role in host defense mechanisms against intracellular bacterial infections. By inducing pyroptosis, infected cells are eliminated, which helps to clear pathogens and alert neighboring immune cells. This process highlights Gasdermin D’s role in orchestrating a rapid and inflammatory response that fights off microbial invaders.
Gasdermin D in Health and Disease
Gasdermin D and the pyroptosis pathway it mediates are involved in maintaining health and contribute to the development of various diseases. In healthy individuals, Gasdermin D is a component of the innate immune system, providing defense against pathogens. Its ability to induce pyroptosis helps eliminate infected cells and release pro-inflammatory signals, which recruit other immune cells to the site of infection. This process supports the body’s ability to combat bacterial, fungal, and viral infections.
However, dysregulated or excessive Gasdermin D activation and pyroptosis can contribute to various disease states linked to chronic inflammation. For instance, Gasdermin D has been implicated in conditions such as sepsis, where widespread inflammatory cell death can lead to tissue damage. It also plays a role in neurodegenerative diseases and nonalcoholic steatohepatitis (NASH). In autoimmune disorders and chronic inflammatory diseases like inflammatory bowel disease (IBD) and multiple sclerosis, Gasdermin D’s activity can exacerbate inflammation and tissue injury.
Gasdermin D’s role in cancer is complex. In some contexts, it can act as a tumor suppressor by promoting the death of cancer cells and stimulating anti-tumor immunity. Pyroptosis can help eliminate tumor cells and reprogram the tumor microenvironment to attract immune cells that fight cancer. However, in other situations, Gasdermin D-mediated inflammation can inadvertently support cancer progression, such as in obesity-related hepatocellular carcinoma. The balance of Gasdermin D activity makes it a promising, yet challenging, target for therapeutic interventions in a range of human diseases.