KANAZAWA UNIVERSITY
IMAGE: Caspase-1, a protease of the caspase family, is activated in response to microbial infections, cellular stresses, and so on, through inflammasome activation, resulting in the maturation of the key pro-inflammatory cytokines IL-1α and IL-1β. Although caspase-1 directly processes pro-IL-1β into the mature form, pro-IL-1α is not a substrate for caspase-1. It has long been unclear why activation of caspase-1 causes the maturation of IL-1α. This study revealed that gasdermin D (GSDMD), an executor of cell death called pyroptosis, mediates IL-1α maturation downstream of caspase-1. Caspase-1 cleaves GSDMD, and its N-terminal fragment forms pores in the cell membrane. This allows the influx of calcium ions, leading to activation of calpains and processing of pro-IL-1α into its mature form by calpains. Maturation of IL-1 not only increases its activity but also facilitates its release from the cell through GSDMD pores. Therefore, GSDMD plays a critical role in caspase-1-dependent inflammatory events, which include the maturation and release of IL-1α. As GSDMD and IL-1α have been implicated in the pathogenesis of several inflammatory diseases, this signaling pathway may be a therapeutic target for such disorders.
CREDIT: KANAZAWA UNIVERSITY
Kanazawa, Japan – Interluekin-1α (IL-1α) is an important part of the immune response, but until now it has been unclear how this molecule is processed from its precursor, pro-IL-1α, and exits the cell during inflammasome activation. Now, researchers from Japan have found that gasdermin D, a protein that was already known to mediate pyroptosis, a form of regulated cell death, plays a crucial role in the maturation and release of IL-1α.
In a study published in March in Cell Reports, researchers from Kanazawa University report that, when the inflammasome (a part of the innate immune system) is activated, gasdermin D forms pores in the cell membrane that allow factors from outside of the cell to flow in, leading to the activation and release of mature IL-1α.
Previous work has shown that inflammasome activation leads to gasdermin D being cut in two by an enzyme and that one-half of the cut protein forms membrane pores. This leads to pyroptosis whereby the pores let water into the cells, causing them to swell and burst.
“We knew that caspase-1 cleaves gasdermin D, and that this enzyme is also important for IL-1α activation,” says the lead author of the study Kohsuke Tsuchiya. “We, therefore, suspected that gasdermin D might be involved in the pathway leading to IL-1α release.”
To test this possibility, the researchers deleted the gene encoding gasdermin D and found that this almost completely eliminated IL-1α exit from the cells. Unexpectedly, though, they also saw that virtually no mature IL-1α was present inside these cells.
“This made us think that gasdermin D is important not only for IL-1α release but also IL-1α maturation,” explains Takashi Suda, lead author of the study. “When we looked into this in more detail, we found that gasdermin D did not need to cause cell lysis for these effects to take place. Instead, only its ability to form pores in the membrane was required for both IL-1α maturation and release.”
The researchers went on to show that pore formation by gasdermin D allows calcium influx and activation of calpains (a type of proteases), which promotes processing of the pro-IL-1α precursor into mature IL-1α maturation.
“Our findings provide the missing link between caspase-1 activity and IL-1α maturation,” says Tsuchiya.
Given that inflammasome activation is a key element of both inflammatory diseases and the response to infection, this study provides important insight into the essential functions of the human immune system. Identifying gasdermin D as a regulator of immune function as well as cell death increases our understanding of how inflammasome activation ultimately leads to IL-1α release from immune cells.
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