Interferons Transcriptionally Up-Regulate MLKL Expression in Cancer Cells

Knuth, Anne-Kathrin; Rösler, Stefanie; Schenk, Barbara; Kowald, Lisa; Wijk, Sjoerd J. L. van; Fulda, Simone

doi:10.1016/j.neo.2018.11.002

Cited by 54 publications

(55 citation statements)

References 44 publications

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“…Recent literature reported that the transcription upregulation of RIPK3 and MLKL were controlled by SP1, STAT1, or CDK9 in various cancer cell lines [60][61][62] and during hepatitis. 63 JAK/STAT signaling pathway has been shown to play dynamic and important roles during muscle regeneration.…”

Section: Discussionmentioning

confidence: 99%

Myofiber necroptosis promotes muscle stem cell proliferation via releasing Tenascin-C during regeneration

et al. 2020

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Necroptosis, a form of programmed cell death, is characterized by the loss of membrane integrity and release of intracellular contents, the execution of which depends on the membrane-disrupting activity of the Mixed Lineage Kinase Domain-Like protein (MLKL) upon its phosphorylation. Here we found myofibers committed MLKL-dependent necroptosis after muscle injury. Either pharmacological inhibition of the necroptosis upstream kinase Receptor Interacting Protein Kinases 1 (RIPK1) or genetic ablation of MLKL expression in myofibers led to significant muscle regeneration defects. By releasing factors into the muscle stem cell (MuSC) microenvironment, necroptotic myofibers facilitated muscle regeneration. Tenascin-C (TNC), released by necroptotic myofibers, was found to be critical for MuSC proliferation. The temporary expression of TNC in myofibers is tightly controlled by necroptosis; the extracellular release of TNC depends on necroptotic membrane rupture. TNC directly activated EGF receptor (EGFR) signaling pathway in MuSCs through its N-terminus assembly domain together with the EGF-like domain. These findings indicate that necroptosis plays a key role in promoting MuSC proliferation to facilitate muscle regeneration.

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Section: Discussionmentioning

confidence: 99%

Myofiber necroptosis promotes muscle stem cell proliferation via releasing Tenascin-C during regeneration

et al. 2020

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“…Interestingly, RIP1/3 can also facilitate inflammasome activation, enabling the stimulation of IL1β and IL18 cytokines [168]. Moreover, there is accumulating evidence that inflammation itself can also regulate necroptosis via cytokines like type I/II IFNs, that can increase the expression of MLKL, which indicates a putative existence of a necroptosis-inflammation auto-fueling loop [169]. However, despite a clear pro-inflammatory phenotype, final immunological outcome of necroptosis may not always be sufficiently immunogenic [158].…”

Section: Necroptosis-driven Modulation Of Immune Responsesmentioning

confidence: 99%

Necroptosis in Immuno-Oncology and Cancer Immunotherapy

Sprooten

Wijngaert

Vanmeerbeek

et al. 2020

Cells

132

112

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Immune-checkpoint blockers (ICBs) have revolutionized oncology and firmly established the subfield of immuno-oncology. Despite this renaissance, a subset of cancer patients remain unresponsive to ICBs due to widespread immuno-resistance. To “break” cancer cell-driven immuno-resistance, researchers have long floated the idea of therapeutically facilitating the immunogenicity of cancer cells by disrupting tumor-associated immuno-tolerance via conventional anticancer therapies. It is well appreciated that anticancer therapies causing immunogenic or inflammatory cell death are best positioned to productively activate anticancer immunity. A large proportion of studies have emphasized the importance of immunogenic apoptosis (i.e., immunogenic cell death or ICD); yet, it has also emerged that necroptosis, a programmed necrotic cell death pathway, can also be immunogenic. Emergence of a proficient immune profile for necroptosis has important implications for cancer because resistance to apoptosis is one of the major hallmarks of tumors. Putative immunogenic or inflammatory characteristics driven by necroptosis can be of great impact in immuno-oncology. However, as is typical for a highly complex and multi-factorial disease like cancer, a clear cause versus consensus relationship on the immunobiology of necroptosis in cancer cells has been tough to establish. In this review, we discuss the various aspects of necroptosis immunobiology with specific focus on immuno-oncology and cancer immunotherapy.

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“…Closer analysis of the genes ascribed to cell death pathways revealed a trend in which the ∆ ist/∆nsm showed slightly higher expression compared to the single ∆ nsm or ∆ ist deletion, suggestive that the parasite requires both effectors to efficiently inhibit the transcription of genes involved in cell death ( Figure 4C). PKR (aka EIF2AK2) and MLKL are known direct targets for interferon induced transcription and are key components in the JAK1/STAT1 signaling cascade responsible for execution of interferon driven necroptosis upon Caspase 8 inhibition (Knuth et al, 2019;Kuhen and Samuel, 1997;Sarhan et al, 2019;Thapa et al, 2013). Given the known ability of T. gondii to block Caspase 8 activity (Payne et al, 2003;Vutova et al, 2007), and the critical roles of PKR and MLKL in necroptosis (Sun et al, 2012;Thapa et al, 2013) we decided to further focus on these two genes.…”

Section: Tgnsm Together With Tgist Inhibit Ifn-γ Induced Necroptoticmentioning

confidence: 99%

Toxoplasma gondiisecreted effectors co-opt host repressor complexes to inhibit necroptosis

Rosenberg

Sibley

2020

Preprint

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SummaryDuring infection, Toxoplasma gondii translocates effector proteins directly into its host cell to subvert various signaling pathways. Here we characterize a novel secreted effector that localizes to the host cell nucleus where it modulates NCoR/SMRT repressor complex levels to repress interferon regulated genes involved in cell death. Type I and type II interferons upregulate many genes including protein kinase R (PKR), inducing formation of the necrosome complex that activates Mixed Lineage Kinase Domain Like Pseudokinase (MLKL) to execute necrotic cell death. Toxoplasma NCoR/SMRT modulator (TgNSM) acts together with another secreted effector TgIST, previously shown to down-modulate IFN-γ signaling to block immune functions. Together TgNSM and TgIST block IFN driven expression of PKR and MLKL, thus preventing host cell necroptotic death. The mechanism of action of TgNSM highlights a previously unappreciated role of NCoR/SMRT in regulation of necroptosis, assuring survival of intracellular cysts, and maintenance of chronic infection.

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Interferons Transcriptionally Up-Regulate MLKL Expression in Cancer Cells

Cited by 54 publications

References 44 publications

Myofiber necroptosis promotes muscle stem cell proliferation via releasing Tenascin-C during regeneration

Myofiber necroptosis promotes muscle stem cell proliferation via releasing Tenascin-C during regeneration

Necroptosis in Immuno-Oncology and Cancer Immunotherapy

Toxoplasma gondiisecreted effectors co-opt host repressor complexes to inhibit necroptosis

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