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, which is phenotypically different from apoptosis, is considered as a lytic form of unregulated and accidental cell death [1]. However, this phenomenon was disproved by showing that the necrosis is 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) is 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 niche and induce protective inflammatory responses to subsequently mount host immune responses [2, 4-6]. Pyroptosis also play an important role in eliciting pro-inflammatory responses to facilitate 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 and viral infections such as Influenza A virus (IAV), HIV-1 and Hepatitis C virus infections [2-6]. For a long time, pyroptosis is considered as a monocytic cell death driven by caspase-1 [3, 6]. Caspase-1 belongs to the inflammatory caspase group and is identified initially as an important factor for the maturation of leaderless pro-inflammatory cytokines (IL-1b and IL-18) [3, 7, 8]. Caspase-1 also found to induce a unique form of cell death (pyroptosis) which is displayed as cell swelling and rupture [4, 5, 9]. Recent studies identified that the inflammatory caspase, caspase-11, is a trigger of pyroptosis, which further led to the discovery of pyroptosis executioner protein, gasdermin D (GSDMD) [3, 10-12]. Research from the past five years appreciate 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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