Virus-mediated inactivation of anti-apoptotic Bcl-2 family members promotes Gasdermin-E-dependent pyroptosis in barrier epithelial cells

Orzalli, Megan H.; Prochera, Aleksandra; Payne, Laurellee; Smith, Avi; Garlick, Jonathan A.; Kagan, Jonathan C.

doi:10.1016/j.immuni.2021.04.012

Cited by 101 publications

(90 citation statements)

References 81 publications

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“…TLR signaling can also induce programmed cell death ( Salaun et al., 2007 ) that contextually can either confer protection from pathogens by eliminating infected cells ( Chow et al., 2016 ; Doerflinger et al., 2020 ; Jorgensen et al., 2017 ; Orzalli et al., 2021 ; Speir et al., 2016 ; Suzuki et al., 2018 ), or increase immunogenic molecules being released from cells, which in some circumstances can cause pathological inflammation and tissue damage ( Wallach et al., 2014 ). Indeed, mammalian genetic variants that increase cell death signaling cause severe inflammation ( Alehashemi and Goldbach-Mansky, 2020 ; Hildebrand et al., 2020 ; Lalaoui et al., 2020 ; Newton et al., 2019a ; Rickard et al., 2014a ; Taraborrelli et al., 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Interferon-γ primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway

et al. 2022

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Cell death plays an important role during pathogen infections. Here, we report that interferon-γ (IFNγ) sensitizes macrophages to Toll-like receptor (TLR)-induced death that requires macrophage-intrinsic death ligands and caspase-8 enzymatic activity, which trigger the mitochondrial apoptotic effectors, BAX and BAK. The pro-apoptotic caspase-8 substrate BID was dispensable for BAX and BAK activation. Instead, caspase-8 reduced pro-survival BCL-2 transcription and increased inducible nitric oxide synthase (iNOS), thus facilitating BAX and BAK signaling. IFNγ-primed, TLR-induced macrophage killing required iNOS, which licensed apoptotic caspase-8 activity and reduced the BAX and BAK inhibitors, A1 and MCL-1. The deletion of iNOS or caspase-8 limited SARS-CoV-2-induced disease in mice, while caspase-8 caused lethality independent of iNOS in a model of hemophagocytic lymphohistiocytosis. These findings reveal that iNOS selectively licenses programmed cell death, which may explain how nitric oxide impacts disease severity in SARS-CoV-2 infection and other iNOS-associated inflammatory conditions.

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Section: Introductionmentioning

confidence: 99%

Interferon-γ primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway

et al. 2022

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“…Relatedly, it has been shown that translation inhibition, a common response to viral infection ( 39 ), in keratinocytes triggers a signaling cascade that results in GSDME-mediated pyroptosis ( Fig. 1A ) ( 40 ). Specifically, virus-mediated translational inhibition results in a decrease of MCL1, an anti-apoptotic BCL2 factor, and inactivation of BCL-xL.…”

Section: Activation Of Mitochondrial Cell Death Pathways During Viral Infectionsmentioning

confidence: 95%

“…(A) Virus-induced inhibition of protein synthesis leads to downregulation and inactivation of anti-apoptotic BCL-2 family members MCL-1 and BCL-xL, respectively. The ensuing mitochondrial damage culminates in caspase-3 cleavage of GSDME and pyroptosis ( 40 ). The HSV-1 ICP27 protein prevents GSDME-mediated pyroptosis by inhibiting caspase-3 through an undefined mechanism ( 40 ).…”

Section: Activation Of Mitochondrial Cell Death Pathways During Viral Infectionsmentioning

confidence: 99%

“…The ensuing mitochondrial damage culminates in caspase-3 cleavage of GSDME and pyroptosis ( 40 ). The HSV-1 ICP27 protein prevents GSDME-mediated pyroptosis by inhibiting caspase-3 through an undefined mechanism ( 40 ). (B) The mitochondrial pathway of apoptosis is initiated by internal stress cues like viral infection.…”

Section: Activation Of Mitochondrial Cell Death Pathways During Viral Infectionsmentioning

confidence: 99%

“…2C ) ( 136 ). As battlegrounds emerge that mold mitochondrial morphology, it is tempting to speculate that future studies may reveal themes related to “altered self,” which serve to indirectly sense pathogen infection at other organelles ( 137 ) and function as defense mechanisms predicted by the guard hypothesis ( 40 , 138 , 139 ).…”

Section: Alterations To Mitochondrial Morphology During Viral Infectionmentioning

confidence: 99%

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Nanomaterials for Disease Treatment by Modulating the Pyroptosis Pathway

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Pyroptosis differs significantly from apoptosis and cell necrosis as an alternative mode of programmed cell death. Its occurrence is mediated by the gasdermin protein, leading to characteristic outcomes including cell swelling, membrane perforation, and release of cell contents. Research underscores the role of pyroptosis in the etiology and progression of many diseases, making it a focus of research intervention as scientists explore ways to regulate pyroptosis pathways in disease management. Despite numerous reviews detailing the relationship between pyroptosis and disease mechanisms, few delve into recent advancements in nanomaterials as a mechanism for modulating the pyroptosis pathway to mitigate disease effects. Therefore, there is an urgent need to fill this gap and elucidate the path for the use of this promising technology in the field of disease treatment. This review article delves into recent developments in nanomaterials for disease management through pyroptosis modulation, details the mechanisms by which drugs interact with pyroptosis pathways, and highlights the promise that nanomaterial research holds in driving forward disease treatment.

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Virus-mediated inactivation of anti-apoptotic Bcl-2 family members promotes Gasdermin-E-dependent pyroptosis in barrier epithelial cells

Cited by 101 publications

References 81 publications

Interferon-γ primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway

Interferon-γ primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway

Mitochondria and Viral Infection: Advances and Emerging Battlefronts

Nanomaterials for Disease Treatment by Modulating the Pyroptosis Pathway

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