Mechanism of gasdermin D recognition by inflammatory caspases and their inhibition by a gasdermin D-derived peptide inhibitor

Yang, Jie; Z, Liu; Wang, Chuanping; Yang, Rui; Rathkey, Joseph K.; Pinkard, Otis; Shi, Wuxian; Chen, Yinghua; Dubyak, George R.; Abbott, Derek W.; Xiao, Tsan Sam

doi:10.1073/pnas.1800562115

Cited by 122 publications

(79 citation statements)

References 38 publications

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“…Recent discoveries surrounding the mechanisms which regulate the expression and activation of IL‐1 family members are also opening possibilities for novel approaches to target these pathways e.g. through NLRP3, protease and gasdermin D/pyroptosis inhibitors . While a greater understanding of the specific, and often unique, roles each family member plays in driving systemic and tissue specific inflammatory responses will expedite these endeavours, some significant gaps in our knowledge still remain.…”

Section: Resultsmentioning

confidence: 99%

Current perspectives on the interleukin‐1 family as targets for inflammatory disease

et al. 2019

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Since the first description of interleukin-1 (IL-1) and the genesis of the field of cytokine biology, the understanding of how IL-1 and related cytokines play central orchestrating roles in the inflammatory response has been an area of intense investigation. As a consequence of these endeavours, specific strategies have been developed to target the function of the IL-1 family in human disease realizing significant impacts for patients. While the most significant advances to date have been associated with inhibition of the prototypical family members IL-1α/β, approaches to target more recently identified family members such as IL-18, IL-33 and the IL-36 subfamily are now beginning to come to fruition. This review summarizes current knowledge surrounding the roles of the IL-1 family in human disease and describes the rationale and strategies which have been developed to target these cytokines to inhibit the pathogenesis of a wide range of diseases in which inflammation plays a centrally important role.Keywords: Canakinumab r Inflammation r Inflammatory disease r Interleukin-1 family r Therapy

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Section: Resultsmentioning

confidence: 99%

Current perspectives on the interleukin‐1 family as targets for inflammatory disease

et al. 2019

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“…The catalytic domain of caspases will directly bind to GSDMD and its cleavage site peptide fltd [80]. Ac-FLTDcmk, a GSDMD-derived peptide inhibitor, can inhibit the cleavage of GSDMD by binding directly to the core catalytic domain of caspase-1, caspase-4, caspase-5, and caspase-11.…”

Section: Therapeutic Prospects Of Targeting Inflammasomes In Renal DImentioning

confidence: 99%

Research Progress on the Role of Inflammasomes in Kidney Disease

Chi

Geng

Liu

et al. 2020

Mediators of Inflammation

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Inflammasomes are multimeric complexes composed of cytoplasmic sensors, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC or PYCARD), and procaspase-1 and play roles in regulating caspase-dependent inflammation and cell death. Inflammasomes are assembled by sensing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and initiate inflammatory responses by activating caspase-1. Activated caspase-1 promotes the release of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18 and eventually induces pyroptosis. Inflammasomes are closely related to kidney diseases. In particular, the NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome has been shown to cause acute and chronic kidney diseases by regulating canonical and noncanonical mechanisms of inflammation. Small-molecule inhibitors that target NLRP3 and other components of the inflammasome are potential options for the treatment of kidney-related diseases such as diabetic nephropathy. This article will focus on the research progress on inflammasomes and the key pathogenic roles of inflammasomes in the development and progression of kidney diseases and explore the potential of this intracellular inflammation to further prevent or block the development of the kidney disease.

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“…GSDMD KO macrophages treated with LPS and nigericin showed that IL-1β release was dependent on GSDMD and that these cells are resistant to pyroptosis. To validate the specificity for GSDMD in mediating IL-1β release, a peptide inhibitor, N-acetyl-Phe-Leu-Thr-Asp-chloromethylketone (Ac-FLTD-CMK) 29 To determine if the caspases specifically interacted with each other, COS-7 cells were transfected with pro-caspase-1, procaspase-4, and pro-IL-1β plasmids. We used COS-7 cells as they are easy to transfect with more than 90% transfection efficiency using GFP and they do not express ASC or NLRP3, facilitating the interactions between the caspases independent of the inflammasome complex (Fig.…”

Section: E Histolytica-induced Gsdmd Cleavage Regulates Il-1β Secretionmentioning

confidence: 99%

Entamoeba histolytica-induced IL-1β secretion is dependent on caspase-4 and gasdermin D

2019

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During invasion, Entamoeba histolytica (Eh) encounter macrophages and activate them to elicit tissue damaging pro-inflammatory responses. When Eh binds macrophages via the Gal-lectin, surface EhCP-A5 RGD sequence ligates α 5 β 1 integrin to activate caspase-1 in a complex known as the NLRP3 inflammasome. In this study, we investigated Eh requirements underlying macrophage caspase-4 and -1 activation and the role caspase-4 and gasdermin D (GSDMD) play in augmenting pro-inflammatory cytokine responses. Caspase-4 activation was similar to caspase-1 requiring live Eh attachment via the Gal-lectin and EhCP-A5. However, unlike caspase-1, caspase-4 activation was independent of ASC and NLRP3. Using CRISPR/Cas9 gene editing of caspase-4 and -1 and GSDMD, we determined that caspase-1 and bioactive IL-1β release was highly dependent on caspase-4 activation and cleavage of GSDMD in response to Eh. Formaldehyde cross-linking to stabilize protein-protein interactions in transfected COS-7 cells stimulated with Eh revealed that caspase-4 specifically interacted with caspase-1 in a protein complex that enhanced the cleavage of caspase-1 CARD domains to augment IL-1β release. Activated caspase-4 and -1 cleaved GSDMD liberating the N-terminal p30 pore-forming fragment that caused the secretion of IL-1β. These findings reveal a novel role for caspase-4 as a sensor molecule to amplify proinflammatory responses when macrophage encounters Eh.

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Mechanism of gasdermin D recognition by inflammatory caspases and their inhibition by a gasdermin D-derived peptide inhibitor

Cited by 122 publications

References 38 publications

Current perspectives on the interleukin‐1 family as targets for inflammatory disease

Current perspectives on the interleukin‐1 family as targets for inflammatory disease

Research Progress on the Role of Inflammasomes in Kidney Disease

Entamoeba histolytica-induced IL-1β secretion is dependent on caspase-4 and gasdermin D

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