Defective pyroptosis

Defective pyroptosis Pyroptosis is a form of lytic inflammatory programmed cell death that is mediated by the pore‑forming gasdermins (GSDMs) (Shi J et al. 2017) to stimulate immune responses through the release of pro‑inflammatory interleukin (IL)‑1β, IL‑18 (mainly in GSDMD-mediated pyroptosis) as well as danger signals such as adenosine triphosphate (ATP) or high mobility group protein B1 (HMGB1) (reviewed in Shi J et al. 2017; Man SM et al. 2017; Tang D et al. 2019; Lieberman J et al. 2019). Pyroptosis protects the host from microbial infection but can also lead to pathological inflammation if overactivated or dysregulated (reviewed in Orning P et al. 2019; Tang L et al. 2020). During infections, the excessive production of cytokines can lead to a cytokine storm, which is associated with acute respiratory distress syndrome (ARDS) and systemic inflammatory response syndrome (SIRS) (reviewed in Tisoncik JR et al. 2012; Karki R et al. 2020; Ragab D et al. 2020). Pyroptosis has a close but complicated relationship to tumorigenesis, affected by tissue type and genetic background. Pyroptosis can trigger potent antitumor immune responses or serve as an effector mechanism in antitumor immunity (Wang Q et al. 2020; Zhou Z et al. 2020; Zhang Z et al. 2020), while in other cases, as a type of proinflammatory death, pyroptosis can contribute to the formation of a microenvironment suitable for tumor cell growth (reviewed in Xia X et al. 2019; Jiang M et al. 2020; Zhang Z et al. 2021).This Reactome module describes the defective GSDME function caused by cancer‑related GSDME mutations (Zhang Z et al. 2020). It also shows epigenetic inactivation of GSDME due to hypermethylation of the GSDME promoter region (Akino K et al. 2007; Kim MS et al. 2008a,b; Croes L et al. 2017, 2018; Ibrahim J et al. 2019). Aberrant promoter methylation is considered to be a hallmark of cancer (Ehrlich M et al. 2002; Dong Y et al. 2014; Lam K et al. 2016; Croes L et al. 2018). Treatment with the DNA methyltransferase inhibitor decitabine (5‑aza‑2'‑deoxycytidine or DAC) may elevate GSDME expression in certain cancer cells (Akino K et al. 2007; Fujikane T et al. 2009; Wang Y et al. 2017).