Meta-Biol

• Pathways

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).

Programmed cell death is frequently impaired in cancer and is thought to significantly contribute to resistance to chemotherapy. Mutations and perturbations in expression of different proteins involved in programmed cell death, such as TP53 (p53), BH3-only family proteins, caspases and their regulators enable malignant cells to evade apoptosis (Ghavami et al. 2009, Chao et al. 2011, Wong 2011, Fernald and Kurokawa 2013, Ichim and Tait 2016).

Biological processes are captured in Reactome by identifying the molecules (DNA, RNA, protein, small molecules) involved in them and describing the details of their interactions. From this molecular viewpoint, human disease pathways have three mechanistic causes: the inclusion of microbially-expressed proteins, altered functions of human proteins, or changed expression levels of otherwise functionally normal human proteins.

The first group encompasses the infectious diseases such as influenza, tuberculosis and HIV infection. The second group involves human proteins modified either by a mutation or by an abnormal post-translational event that produces an aberrant protein with a novel function. Examples include somatic mutations of EGFR and FGFR (epidermal and fibroblast growth factor receptor) genes, which encode constitutively active receptors that signal even in the absence of their ligands, or the somatic mutation of IDH1 (isocitrate dehydrogenase 1) that leads to an enzyme active on 2-oxoglutarate rather than isocitrate, or the abnormal protein aggregations of amyloidosis which lead to diseases such as Alzheimer's.

Infectious diseases are represented in Reactome as microbial-human protein interactions and the consequent events. The existence of variant proteins and their association with disease-specific biological processes is represented by inclusion of the modified protein in a new or variant reaction, an extension to the 'normal' pathway. Diseases which result from proteins performing their normal functions but at abnormal rates can also be captured, though less directly. Many mutant alleles encode proteins that retain their normal functions but have abnormal stabilities or catalytic efficiencies, leading to normal reactions that proceed to abnormal extents. The phenotypes of such diseases can be revealed when pathway annotations are combined with expression or rate data from other sources.

Depending on the biological pathway/process immediately affected by disease-causing gene variants, non-infectious diseases in Reactome are organized into diseases of signal transduction by growth factore receptors and second messengers, diseases of mitotic cell cycle, diseases of cellular response to stress, diseases of programmed cell death, diseases of DNA repair, disorders of transmembrane transporters, diseases of metabolism, diseases of immune system, diseases of neuronal system, disorders of developmental biology, disorders of extracellular matrix organization, and diseases of hemostatis.