During inflammation, the inflammatory caspase?1 (CASP1) can ...

created [InstanceEdit:9716268] Shamovsky, Veronica, 2021-02-19
dbId 9716221
displayName During inflammation, the inflammatory caspase?1 (CASP1) can ...
literatureReference
modified [InstanceEdit:9716277] Shamovsky, Veronica, 2021-02-20
schemaClass Summation
text During inflammation, the inflammatory caspase?1 (CASP1) can be activated downstream of canonical inflammasome activation in response to sensing of pathogen?derived particles or host?derived danger signals (reviewed in Kelley N et al. 2019; Zheng D et al. 2020). The non?canonical inflammasome assembly is mediated by CASP4, CASP5 in humans and CASP11 in mice upon sensing intracellular bacterial lipopolysaccharide (LPS) (Vigano E et al. 2015; Kayagaki N et al. 2015). Activated inflammatory caspases induce a proinflammatory cell death known as pyroptosis via the proteolytic processing of gasdermin D (GSDMD) (Shi J et al. 2015; Kayagaki N et al. 2015; He W et al. 2015; Ding J et al. 2016; Liu X et al. 2016; Sborgi L et al. EMBO J 2016). Intact GSDMD cannot form pores due to the inhibitory function of its C-terminal domain. Caspase?mediated cleavage of GSDMD releases the C?terminal fragment of GSDMD (276?484) (Shi J et al. 2015), enabling the N?terminal fragment of GSDMD (1?275) to form pores in cellular membranes leading to cytokine release and pyroptosis (Ding J et al. 2016; Liu X et al. 2016; Sborgi L et al. 2016; Mulvihill E et al. 2018). Dimethyl fumarate (DMF, trade name:Tecfidera®) was found to modify ?ys191 of GSDMD to form S-(2-succinyl)-cysteine, a process known as succination of proteins (Humphries F et al. 2020). Cys191 in human GSDMD (corresponding to Cys192 in mouse) is thought to be critical for the GSDMD oligomerization and pore formation (reviewed in Pandeya A et al. 2019). DMF inhibited cell death and lactate dehydrogenase (LDH) release in LPS-primed mouse macrophages and human monocyte-like THP-1 cell in response to nigericin. Similarly, two fumarate analogs, diroximel fumarate (trade name: Vumerity®) and tepilamide fumarate, also blocked LPS-nigericin-induced pyroptosis and formation of GSDMD (1?275) (Humphries F et al. 2020). Treatment with DMF is thought to inhibit the interaction of GSDMD with CASP1, cleavage by CASP1 and oligomerization of GSDMD (Humphries F et al. 2020). Moreover, GSDMD?mediated pyroptosis when overactivated can lead to sepsis. Elevated levels of GSDMD were noted in microparticles isolated from plasma of septic patients (Homsy E et al. 2019). In the murine sepsis model, Gsdmd?deficient mice showed significantly improved survival compared to the wild type mice (Kambara H et al. 2018). Treatment with fumarate protected mice from LPS?induced septic shock (Humphries F et al. 2020). In addition, Gsdmd-/- mice are protected from disease in mouse models of familial Mediterranean fever and multiple sclerosis (MS) (Kanneganti A et al. 2018; Li S et al. 2019). Administration of DMF reduced GSDMD-driven responses in these mouse models (Humphries F et al. 2020). Further, DMF reduced levels of both interleukin (IL)-1? and GSDMD (1?275) in peripheral blood mononuclear cells (PBMCs) from patients with MS. The data suggest that DMF blocks GSDMD pore formation and pyroptosis by modifying Cys191 of GSDMD (Humphries F et al. 2020). Endogenous fumarate may also inactivate GSDMD by succinating Cys191 (Humphries F et al. 2020).

This Reactome event shows the covalent modification of GSDMD, namely S-(2-succinyl)-Cys191-GSDMD, formed by a Michael addition reaction between DMF and the reactive thiol group on Cys191 of GSDMD.

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