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Details on Person During inflammation, the inflammatory caspase‑1 (CASP1) can ...
| Class:Id | Summation:9716221 |
|---|---|
| _displayName | During inflammation, the inflammatory caspase‑1 (CASP1) can ... |
| _timestamp | 2021-02-20 01:47:07 |
| created | [InstanceEdit:9716268] Shamovsky, Veronica, 2021-02-19 |
| literatureReference | [LiteratureReference:9647669] Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death [LiteratureReference:9647685] Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores [LiteratureReference:9647674] Pore-forming activity and structural autoinhibition of the gasdermin family [LiteratureReference:9647662] GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death [LiteratureReference:9693533] Mechanism of membrane pore formation by human gasdermin-D [LiteratureReference:9710056] Gasdermin D (GSDMD) as a new target for the treatment of infection [LiteratureReference:9710046] Circulating Gasdermin-D in Critically Ill Patients [LiteratureReference:9686131] Human caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes [LiteratureReference:9710049] Gasdermin D Exerts Anti-inflammatory Effects by Promoting Neutrophil Death [LiteratureReference:9708036] Inflammasome activation and regulation: toward a better understanding of complex mechanisms [LiteratureReference:9710062] The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation [LiteratureReference:9710236] Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion [LiteratureReference:9716211] Succination inactivates gasdermin D and blocks pyroptosis [LiteratureReference:9716215] Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling [LiteratureReference:9716264] GSDMD is critical for autoinflammatory pathology in a mouse model of Familial Mediterranean Fever [LiteratureReference:9716250] Gasdermin D in peripheral myeloid cells drives neuroinflammation in experimental autoimmune encephalomyelitis |
| modified | [InstanceEdit:9716277] Shamovsky, Veronica, 2021-02-20 |
| 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 Сys191 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)-1β 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. |
| (summation) | [Reaction:9716258] Dimethyl fumarate modifies Cys191 in GSDMD [Homo sapiens] |
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