Transcriptional profiling of HT-29 cells with different treatments
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE108621 | GEO | 2018/06/04
REPOSITORIES: GEO
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Project description:Dynamic control of ubiquitination by deubiquitinating enzymes is essential for almost all biological processes. Ubiquitin-specific peptidase 22 (USP22) is part of the SAGA complex and catalyzes the removal of monoubiquitination from histone H2B, thereby regulating gene transcription. However, novel roles for USP22 have recently emerged, such as tumor development and cell death. Apart from apoptosis, the relevance of USP22 in other programmed cell death pathways still remains unclear. Here, we describe a novel role for USP22 in controlling necroptotic cell death in a variety of tumor cell lines. Loss of USP22 expression significantly delays TNF/Smac mimetic/zVAD.fmk (TBZ)-induced necroptosis, without affecting TNF-mediated NF-B activation or extrinsic apoptosis. Mass-spectrometric ubiquitin remnant profiling identified lysine 518 of Receptor-interacting protein kinase 3 (RIPK3) as USP22-dependent ubiquitination target during necroptosis induction. Mutation of K518 in RIPK3 reduced necroptosisassociated RIPK3 ubiquitination and amplified necrosome formation and necroptotic cell death. In conclusion, we identify a novel role of USP22 in necroptosis and further elucidate the relevance of ubiquitination as crucial regulator of necroptotic cell death.
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Project description:Necroptosis is a newly discovered form of programmed cell death (PCD) showing necrotic features, including membrane permeabilization and the release of damage-associated molecular patterns (DAMPs). Studies have revealed both its tumorigenic role and therapeutic potential in various cancers, yet its impact on head and neck squamous cell carcinoma (HNSCC) is poorly understood. To investigate the differential composition of necroptotic DAMPs, SCC25 cells treated by TNF-α+Smac mimetic (TS), TNF-α+Smac mimetic+zVAD-fmk (TSZ) and Freeze-Thaw (FT) to induce apoptosis, necroptosis and necrosis respectively. Mass spectrum analysis was used to compare the differential compositions among DAMPs derived from apoptosis (TS), necroptosis (TSZ) and necrosis (FT).
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Project description:To determine the role of RIPK1 kinase-dependent transcriptional signaling in microglia and astrocytes, we stimulated cells with RIPK1 kinase-activating stimuli TNF/5z-7 and TNF/Smac/zVAD in the presence or absence of the RIPK1 kinase inhibitor Nec-1s. We identified various genes modulated in a RIPK1 kinase-dependent manner with each stimulation in both microglia and astrocytes, and the main biological pathways were related to an inflammatory and immune response. We identified many cytokines and chemokines upregulated in both microglia and astrocytes upon RIPK1 kinase activation, demonstrating the contribution of RIPK1 kinase signaling to pro-inflammatory responses in microglia and astrocytes
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Project description:Necroptosis is a form of programmed cell death that is defined by activation of the kinase RIPK3, and subsequent cell membrane permeabilization by the effector MLKL. In addition to triggering cell death, RIPK3 activation can promote immune responses through the production of cytokines and chemokines. How active cytokine production is coordinated with the terminal process of necroptosis is unclear. Here, we report that cytokine production continues within necroptotic cells after cells have lost plasma membrane integrity and irreversibly commited to death. The continued production of inflammatory mediators was dependent on mRNA translation, and required maintanence of endoplasmic reticulum integrity, which remained in tact after plasma membrane integrity was lost. The continued translation of cytokines by cellular corpses contributed to necroptotic cell uptake by innate immune cells, as well as priming of adaptive immune responses to antigens associated with necroptotic corpses. These findings imply that necroptosis may represent a program in which cell death and production of inflammatory mediators are coordinated to optimize the immunogenicity of necroptotic cells.
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Project description:Necroptosis is a lytic form of regulated cell death reported to contribute to inflammatory diseases of the gut, skin and lung, as well as ischemic-reperfusion injuries of the kidney, heart and brain. However, precise identification of the cells and tissues that undergo necroptotic cell death in vivo has proven challenging in the absence of robust protocols for immunohistochemical detection. Here, we provide automated immunohistochemistry protocols to detect core necroptosis regulators – Caspase-8, RIPK1, RIPK3 and MLKL – in formalin-fixed mouse and human tissues. We observed surprising heterogeneity in protein expression within tissues, whereby short-lived immune barrier cells were replete with necroptotic effectors, whereas long-lived cells lacked RIPK3 or MLKL expression. Local changes in the expression of necroptotic effectors occurred in response to insults such as inflammation, dysbiosis or immune challenge, consistent with necroptosis being dysregulated in disease contexts. These methods will facilitate the precise localisation and evaluation of necroptotic signaling in vivo.
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Project description:Necroptosis is a regulated but inflammatory form of cell death. We and others have previously reported that necroptotic cells release extracellular vesicles (EVs). We found that necroptotic EVs are loaded with proteins, including the key necroptosis executor factor, phosphorylated mixed lineage kinase domain-like (pMLKL). However, the exact necroptotic EVs proteins composition and impact have not been delineated yet. To characterize their content, EVs from necroptotic and untreated U937 cells were isolated by ultracentrifugation and analyzed by mass spectrometry. A total of 3337 proteins were identified, sharing high similarity with exosome proteome databases. Unsupervised hierarchical clustering of identified proteins distinguished between necroptotic and control EVs. A total of 353 proteins was significantly upregulated in the necroptotic EVs. Among these are MLKL and caspase-8, as validated by immunoblot. Components of ESCRTIII machinery and inflammatory signaling were found to be enriched in the necroptotic EVs, as well as yet unreported components of vesicles formation and transport and necroptosis signaling pathways. Moreover, we show that necroptotic EVs can be phagocytosed by macrophages to modulate cytokine and chemokine secretion. Finally, we reveal that necroptotic EVs contain tumor neoantigen and are enriched with proteins annotated as “antigen processing and presentation” biological process. In summary, our study reveals a new layer of regulation during the early stage of necroptosis by the secretion of specific EVs that influence their microenvironment and may instigate innate and adaptive immune responses. Future investigation will shed light on new players in the necroptosis signaling and its related EVs, and will uncover the functional tasks accomplished by the cargo of these necroptotic EVs.
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Project description:COVID-19 has rapidly circulated around the globe and caused significant morbidity and mortality. The disease is characterized by excessive production of pro-inflammatory cytokines and acute lung damage and patient mortality. Although initial cytokine cascades may be beneficial to the host for clearing the virus, enhanced production of pro-inflammatory cytokines and increasing levels in the systemic circulation, referred to as cytokine storm, can promote tissue damage by inducing inflammatory cell death in both infected and bystander cells. Of the multiple inflammatory cytokines produced by innate immune cells during SARS-CoV-2 infection, we found that the combination of TNF-α and IFN-γ specifically induced cell death characterized by GSDME¬–mediated pyroptosis, caspase-8–mediated apoptosis, and MLKL–mediated necroptosis. Cells deficient in both RIPK3 and caspase-8 or RIPK3 and FADD were resistant to this cell death. However, deletion of pyroptosis, apoptosis, or necroptosis individually was not sufficient to protect against cell death. Mechanistically, the STAT1/IRF1 axis activated by TNF-α and IFN-γ co-treatment induced iNOS for the production of nitric oxide. Pharmacological and genetic deletion of this pathway inhibited pyroptosis, apoptosis, and necroptosis in macrophages. Moreover, inhibition of inflammatory cell death protected mice from TNF-α and IFN-γ–induced lethal cytokine shock that mirrors the pathological symptoms of COVID-19. To determine the physiological relevance of protection, we neutralized both TNF-α and IFN-γ in multiple disease models associated with cytokine storm and found that this treatment provided substantial protection against not only SARS-CoV-2 infection, but also sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock models. Collectively, our findings reveal that blocking the COVID-19 cytokine-mediated inflammatory cell death signaling pathway identified in this study may benefit patients with COVID-19 or other cytokine storm-driven syndromes by limiting inflammation and tissue damage. Additionally, these results open new avenues for the treatment of other infectious and autoinflammatory diseases and cancer where TNF-α and IFN-γ synergism play key pathological roles.
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