Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection

By Joseph Sarhan, Beiyun C. Liu, Hayley I. Muendlein, Peng Li, R. Nilson, Amy Y. Tang, A. Rongvaux, S. Bunnell, F. Shao, Douglas R. Green and 1 more. Proceedings of the National Academy of Sciences of the United States of America, 2018

794 citations recorded by the source corpus.

Significance Here we demonstrate that Yersinia YopJ-induced murine macrophage death involves caspase-8–induced cleavage of both gasdermin D (GSDMD) and gasdermin E (GSDME). The ensuing cell death is rapid, morphologically is similar to pyroptosis, and induces IL-1 release. Recently, both GSDMD and GSDME were reported to be critical effectors of caspase-1/11–driven pyroptosis and caspase-3–dependent secondary necrosis, which prompted the redefinition of pyroptosis as cell death-mediated by gasdermin activation. Our work extends these studies and shows that activation of caspase-8 in the context of TAK1 inhibition results in cleavage of both GSDMD and GSDME, leading to pyroptotic-like cell death. Further study will be needed to determine whether caspase-8 cleaves GSDMD directly or via intermediate substrates. Cell death and inflammation are intimately linked during Yersinia infection. Pathogenic Yersinia inhibits the MAP kinase TGFβ-activated kinase 1 (TAK1) via the effector YopJ, thereby silencing cytokine expression while activating caspase-8–mediated cell death. Here, using Yersinia pseudotuberculosis in corroboration with costimulation of lipopolysaccharide and (5Z)-7-Oxozeaenol, a small-molecule inhibitor of TAK1, we show that caspase-8 activation during TAK1 inhibition results in cleavage of both gasdermin D (GSDMD) and gasdermin E (GSDME) in murine macrophages, resulting in pyroptosis. Loss of GsdmD delays membrane rupture, reverting the cell-death morphology to apoptosis. We found that the Yersinia-driven IL-1 response arises from asynchrony of macrophage death during bulk infections in which two cellular populations are required to provide signal 1 and signal 2 for IL-1α/β release. Furthermore, we found that human macrophages are resistant to YopJ-mediated pyroptosis, with dampened IL-1β production. Our results uncover a form of caspase-8–mediated pyroptosis and suggest a hypothesis for the increased sensitivity of humans to Yersinia infection compared with the rodent reservoir.

Subfields: Immunology, Molecular Biology, Nephrology

View Paper: https://www.semanticscholar.org/paper/d009b19b6273a7d9b1763b7ced43208cd1136821

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Citations in the corpus

Caspases in cell death, inflammation and disease (2019, background): “A mechanistic model is emerging in which the necrosome that contains caspase-8, RIPK1 and RIPK3 acts as a central hub for the integration of inflammasome and cell death responses that are triggered by a broad suite of agents that alter MAP kinase and NF-κB signalling cascades in macrophages, for ins”
Pyroptosis in inflammatory diseases and cancer (2022, background): “Another apoptotic caspase that can trigger pyroptosis is caspase-8, which can induce the cleavage of GSDMD to elicit pyroptosis during Yersinia infection [17, 40].”
Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis. (2020, background): “Caspase-8 may also cleave GSDMD at the FLTD site (Orning et al., 2018; Sarhan et al., 2018), and caspase-3 cleaves GSDME at a DMPD site to induce pyroptosis (Rogers et al.”
Caspases in Cell Death, Inflammation, and Gasdermin-Induced Pyroptosis (2020, background): “Caspase-8, in addition to caspase-1 or caspase-4/-5/-11, directly regulates cleavage and activation of gasdermin proteins to induce pyroptosis (172, 173).”
ZBP1 and TAK1: Master Regulators of NLRP3 Inflammasome/Pyroptosis, Apoptosis, and Necroptosis (PAN-optosis) (2019, background): “Furthermore, recent studies focused on pharmacological- or pathogen-based inhibition of TAK1 have revealed a direct role for caspase-8, which is activated in the RIPK1–FADD–caspase-8 complex, in driving GSDMD cleavage and pyroptosis, independent of caspase-1 (Orning et al., 2018; Sarhan et al., 2018”
From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways (2021, background): “Furthermore, TAK1 inhibition, which can be induced by the Yersinia effector YopJ, initiates cell death characterized by pyroptosis, apoptosis and necroptosis [35,36], and CASP8 can directly activate GSDMD in this context [89–91].”