Pathogen blockade of TAK1 triggers caspase-8 dependent cleavage of Gasdermin D and cell death

By Pontus Orning, D. Weng, K. Starheim, D. Ratner, Z. Best, Bettina L. Lee, A. Brooks, S. Xia, Hao Wu, M. Kelliher and 8 more. Science, 2018

894 citations recorded by the source corpus.

Caspase-8 is a player in pyroptosis The activation of certain pattern-recognition receptors by pathogen-associated molecular patterns results in the formation of inflammasome complexes. Inflammasome complexes can initiate both the maturation of inflammatory cytokines and pyroptotic cell death via the caspase-mediated cleavage of gasdermin D (GSDMD). As of now, the only known regulators of GSDMD in macrophages are caspase-1 and caspase-11. Orning et al. report an additional pathway controlling GSDMD processing. YopJ, an effector molecule produced by Yersinia (the causative agent of plague), inhibits TAK1–IκB kinase signaling. This, in turn, results in caspase-8–directed cleavage of GSDMD, pyroptosis, and the release of interleukin 1β (IL-1β) and IL-18. Thus, in the arms race between host and pathogen, the host recognizes signaling disturbances as pathogenic and counters with inflammation and cell death. Science, this issue p. 1064 Bacterial blockade of key host signaling pathways triggers pyroptosis and inflammation. Limited proteolysis of gasdermin D (GSDMD) generates an N-terminal pore-forming fragment that controls pyroptosis in macrophages. GSDMD is processed via inflammasome-activated caspase-1 or -11. It is currently unknown whether macrophage GSDMD can be processed by other mechanisms. Here, we describe an additional pathway controlling GSDMD processing. The inhibition of TAK1 or IκB kinase (IKK) by the Yersinia effector protein YopJ elicits RIPK1- and caspase-8–dependent cleavage of GSDMD, which subsequently results in cell death. GSDMD processing also contributes to the NLRP3 inflammasome–dependent release of interleukin-1β (IL-1β). Thus, caspase-8 acts as a regulator of GSDMD-driven cell death. Furthermore, this study establishes the importance of TAK1 and IKK activity in the control of GSDMD cleavage and cytotoxicity.

Subfields: Immunology, Molecular Biology, Nephrology

View Paper: https://www.semanticscholar.org/paper/2188b46e07abae83b8517ef1266083a83759619d

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In Immunology

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In Molecular Biology

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2. Yaqiu Wang
3. R. Malireddi
4. S. Kesavardhana
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In Nephrology

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Citations in the corpus

• Caspases in cell death, inflammation and disease (2019, neutral): “enterocolitica (Orning et al., 2018; Philip et al., 2014; Sarhan et al., 2018; Weng et al., 2014), Candida albicans (Ganesan et al.”
• 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”
• 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).”
• 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].”
• An update on the regulatory mechanisms of NLRP3 inflammasome activation (2021, background): “also reported RIPK1- and caspase-8–dependent cleavage of GSDMD, resulting in pyroptosis and the release of IL1β and IL-18 by inhibiting TAK1–IκB kinase signaling with the Yersinia effector protein YopJ.(162) Interestingly, TLR priming that mimics pathogen-mediated priming triggers RIPK1 kinase activ”
• Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes (2020, neutral): “Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells.”
• 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].”