Figure (IMAGE)
Caption
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 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 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.
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Kanazawa University
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