Death of Eukaryotic Cell

“In physiological settings, intrinsic genetic programs allow eukaryotic cells to commit suicide in a regulated manner. The best-studied programmed cell death is apoptosis, which is regulated by cysteine-aspartic proteases called caspases. Apoptosis is crucial for the development of an organism and is immunologically silent due to the containment of intracellular contents, which do not elicit inflammation. Necrosis, phenotypically different from apoptosis, is considered a lytic form of unregulated and accidental cell death [1]. However, this idea was disproven, demonstrating that necrosis is a molecularly controlled form of cell death called ‘inflammatory cell death’ [1, 2]. Inflammatory cell death is phenotypically distinct from classical programmed apoptosis and appears phenotypically similar to necrosis. Inflammatory cell death pathways are emerging as a central component of inflammation in the pathogenesis of several human diseases [1-3]. Necroptosis and pyroptosis are two different forms of inflammatory cell death pathways that are widely studied.

During infection, clearance of an infected cell is critical to maintain organismal homeostasis. Pyroptosis (Pyro-fire; ptosis-falling) has emerged as a major form of programmed cell death in vertebrates during pathogenic infections [2, 3]. It is specifically induced in infected cells to potentially eliminate pathogenic niches and induce protective inflammatory responses, which subsequently mount host immune responses [2, 4-6]. Pyroptosis also plays an essential role in eliciting pro-inflammatory responses to facilitate a high surge of innate immune cells to the site of injury or infection. Pyroptosis is activated in various bacterial infections such as Francisella, Legionella, Shigella, and Salmonella, as well as viral infections such as Influenza A virus (IAV), HIV-1, and Hepatitis C virus infections [2-6]. For a long time, pyroptosis was considered as a monocytic cell death driven by caspase-1 [3, 6]. Caspase-1 belongs to the inflammatory caspase group and was initially identified as an essential factor for the maturation of leaderless pro-inflammatory cytokines (IL-1b and IL-18) [3, 7, 8]. Caspase-1 was also found to induce a unique form of cell death (pyroptosis) displayed as cell swelling and rupture [4, 5, 9]. Recent studies identified that the inflammatory caspase, caspase-11, triggers pyroptosis, which further led to the discovery of the pyroptosis executioner protein, gasdermin D (GSDMD) [3, 10-12]. Research from the past five years appreciates the crucial function of gasdermin-induced pyroptosis in disease by discovering its mechanisms of activation and execution. In this review, we will provide insights into the pyroptosis activation, mechanism of its execution by gasdermin proteins, and a structural perspective of gasdermin regulation. We also discuss the current knowledge on in vivo functions of Gasdermin D in different disease settings and describe the emerging regulatory mechanisms of gasdermin-induced pyroptosis.”

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