Molecular mechanism of RIPK1 and caspase-8 in homeostatic type I interferon production and regulation

Wang, Yaqiu; Karki, Rajendra; Mall, Raghvendra; Sharma, Bhesh Raj; Kalathur, Ravi C.; Lee, SangJoon; Kancharana, Balabhaskararao; So, Matthew; Combs, Katie L.; Kanneganti, Thirumala‐Devi

doi:10.1016/j.celrep.2022.111434

Cited by 12 publications

(3 citation statements)

References 90 publications

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“…Aside from the here discovered causal role of oncogenic KRAS itself in driving an IFN response, caspase 8 or FADD deletion were shown to induce ZBP1-expression and -dependent necroptosis through a cGAS/STING-mediated pathway 63 . Along similar lines, absence of caspase 8 may additionally unleash RIPK1/TBK1dependent induction of an IFN response 64 which may contribute towards the oncogenic KRASinduced IFN response we observed here upon caspase 8 deletion in vivo. However, we find that aside from the IFN response induced by oncogenic KRAS caspase 8 is co-upregulated through selection thereby keeping cells alive but in a necroptotically primed state.…”

Section: Discussionsupporting

confidence: 66%

Caspase 8 protects pancreatic neoplasia from KRAS-driven necroptotic priming

Tishina,

Dahlhaus,

Androulidaki

et al. 2023

Preprint

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Caspase 8 regulates normal tissue homeostasis by executing apoptosis and protecting from necroptosis. Several aggressive cancers express high levels of caspase 8, yet its function in neoplastic disease remains poorly explored. Here, we find that oncogenic KRAS-driven neoplastic transformation induces a transcriptional state of necroptotic priming, but necroptosis itself is kept in check by co-upregulation of caspase 8. Mice in which caspase 8 is deleted in the pancreas manifested a drastic decrease in precursor lesion formation in a KRASG12D-driven model of pancreatic cancer. Co-deletion of the essential necroptosis effector MLKL reversed the protective effects of caspase 8 ablation, and promoted metastasis. Mechanistically, oncogenic KRAS induced a STING-dependent type I interferon response, resulting in upregulation of necroptosis pathway components. High caspase 8 expression in precursor lesions was a result of co-selection to prevent necroptosis. Therefore, triggering necroptosis by blocking caspase 8 activity was therapeutically highly efficacious in models of genetically engineered PDAC in vivo. These results assign a tumor-protective function to caspase 8 in PDAC and show that overcoming caspase 8 activity has therapeutic benefit in this incurable malignancy.

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Section: Discussionsupporting

confidence: 66%

Caspase 8 protects pancreatic neoplasia from KRAS-driven necroptotic priming

Tishina,

Dahlhaus,

Androulidaki

et al. 2023

Preprint

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“…50,51 Moreover, caspase-8 is important for negatively regulating type I IFN via hindering the RIPK1-TBK1 signaling during homeostasis. 52 Under deletion or suppression of caspase-8, RIPK1 drives increased IFN formation via interaction with TBK1. 53 The combined loss of caspase-8 and RIPK1 attenuates type I IFN, uncovering the significance of RIPK1 in such event.…”

Section: Ripk1-panoptosomementioning

confidence: 99%

“…During apoptotic process, caspases‐9/‐3 inhibit cGAS‐STING‐based type I IFN generation 50,51 . Moreover, caspase‐8 is important for negatively regulating type I IFN via hindering the RIPK1‐TBK1 signaling during homeostasis 52 . Under deletion or suppression of caspase‐8, RIPK1 drives increased IFN formation via interaction with TBK1 53 .…”

Section: Components and Modulation Of The Panoptosome Complexesmentioning

confidence: 99%

PANoptosis: Mechanisms, biology, and role in disease

Sun,

Yang,

Meng

et al. 2023

Immunological Reviews

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SummaryCell death can be executed through distinct subroutines. PANoptosis is a unique inflammatory cell death modality involving the interactions between pyroptosis, apoptosis, and necroptosis, which can be mediated by multifaceted PANoptosome complexes assembled via integrating components from other cell death modalities. There is growing interest in the process and function of PANoptosis. Accumulating evidence suggests that PANoptosis occurs under diverse stimuli, for example, viral or bacterial infection, cytokine storm, and cancer. Given the impact of PANoptosis across the disease spectrum, this review briefly describes the relationships between pyroptosis, apoptosis, and necroptosis, highlights the key molecules in PANoptosome formation and PANoptosis activation, and outlines the multifaceted roles of PANoptosis in diseases together with a potential for therapeutic targeting. We also discuss important concepts and pressing issues for future PANoptosis research. Improved understanding of PANoptosis and its mechanisms is crucial for identifying novel therapeutic targets and strategies.

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Defining PANoptosis: Biochemical and Mechanistic Evaluation of Innate Immune Cell Death Activation

Tweedell,

Hibler,

Kanneganti

2024

Current Protocols

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The innate immune system is the first line of host defense. Innate immune activation utilizes pattern recognition receptors to detect pathogens, pathogen‐associated and damage‐associated molecular patterns (PAMPs and DAMPs), and homeostatic alterations and drives inflammatory signaling pathways and regulated cell death. Cell death activation is critical to eliminate pathogens and aberrant or damaged cells, while excess activation can be linked to inflammation, tissue damage, and disease. Therefore, there is increasing interest in studying cell death mechanisms to understand the underlying biology and identify therapeutic strategies. However, there are significant technical challenges, as many cell death pathways share key molecules with each other, and genetic models where these cell death molecules are deleted remain the gold standard for evaluation. Furthermore, extensive crosstalk has been identified between the cell death pathways pyroptosis, apoptosis, necroptosis, and the more recently characterized PANoptosis, which is defined as a prominent, unique innate immune, lytic, and inflammatory cell death pathway initiated by innate immune sensors and driven by caspases and RIPKs through PANoptosomes. PANoptosomes are multi‐protein complexes assembled by innate immune sensor(s) in response to pathogens, PAMPs, DAMPs, cytokines, and homeostatic changes that drive PANoptosis. In this article, we provide methods for molecularly defining distinct cell death pathways, including PANoptosis, using both genetic and chemical approaches through western blot, LDH assay, and microscopy readouts. This procedure allows for the assessment of cell death on the cell population and single‐cell levels even without access to genetic models. Having this comprehensive workflow that is more accessible to all labs will improve our ability as a scientific community to accelerate discovery. Using these protocols will help identify new innate immune sensors that drive PANoptosis and define the molecular mechanisms and regulators involved to establish new targets for clinical translation. © 2024 The Author(s). Current Protocols published by Wiley Periodicals LLC.Basic Protocol 1: Induction and quantification of cell death using live cell imagingAlternate Protocol 1: Quantification of cell death using LDHAlternate Protocol 2: Assessment of cell death complexes in single cells using immunofluorescence stainingBasic Protocol 2: Analysis of cell death mechanisms by immunoblots (western blots)

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Molecular mechanism of RIPK1 and caspase-8 in homeostatic type I interferon production and regulation

Cited by 12 publications

References 90 publications

Caspase 8 protects pancreatic neoplasia from KRAS-driven necroptotic priming

Caspase 8 protects pancreatic neoplasia from KRAS-driven necroptotic priming

PANoptosis: Mechanisms, biology, and role in disease

Defining PANoptosis: Biochemical and Mechanistic Evaluation of Innate Immune Cell Death Activation

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