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Articles by John Silke
Reply to ‘Single-cell evidence for PANoptosome complexes’
In their Correspondence to our Comment (Vince, J. E. & Silke, J. The PANoptosis hypothesis examined. Nat. Rev. Mol. Cell Biol. https://doi.org/10.1038/s41580-026-00970-4; 2026)1, Tweedell and Kanneganti contend that PANoptosis is a distinct cell death pathway (Tweedell, R. & Kanneganti, T.-D. Single-cell evidence for PANoptosome complexes. Nat. Rev. Mol. Cell Biol.
The transmembrane domain structure of TNFR1 suppresses ligand-independent autoactivation but is not required for TNF-induced signaling
Editor’s summary Signaling by the cytokine TNF mediates immune responses to infections, and its dysregulation underlies numerous inflammatory disorders. Binding of trimeric TNF to its receptor TNFR1 stimulates signaling by trimeric and higher-order TNFR1. Noting that the transmembrane domains (TMDs) of other TNFR superfamily members support ligand-dependent receptor activation, Wang et al.
The PANoptosis hypothesis examined
Danger signals have been reported to induce a PANoptosome complex, enabling the simultaneous induction of pyroptotic, apoptotic and necroptotic cell death. Here, we discuss the evidence for PANoptosis and suggest criteria to distinguish it from other hypotheses that can account for activation of multiple cell death pathways.
The kinase domain of RIPK3 tunes its scaffolding functions - Cell Death & Differentiation
Abstract The pro-inflammatory programmed cell death pathway, necroptosis, relies on phosphorylation of the terminal effector, MLKL, by RIPK3. RIPK3-deficient mice or those harboring the kinase-inactivating mutation, RIPK3K51A, are ostensibly normal in the absence of challenge, indicating that RIPK3 and its kinase activity are dispensable for development. However, another kinase-inactivating mutation, RIPK3D161N, results in embryonic lethality in mice due to widespread apoptosis.
Expanding the toolbox to develop IAP-based degraders of TEAD transcription factors - Communications Chemistry
Abstract The TEAD transcription factors (TEAD1-4) are critical effectors of the Hippo pathway, forming active nuclear complexes with transcriptional co-activators YAP/TAZ to regulate cell growth/apoptosis pathways and control fundamental processes such as organ size. Frequent dysregulation of the Hippo pathway in cancer and the presence of druggable binding sites on TEADs make them attractive targets for development of small molecule inhibitors and degraders.
SIX of one and half-a-dozen USP2 regulating inflammation - Cell Research
You have full access to this article via your institution. The sine oculis (SIX) transcription factors prevent excessive inflammatory responses. Yi et al. now show that their levels are regulated by a deubiquitinase, USP2, that is upregulated by inflammatory stimuli and prevents proteasomal turnover of SIX proteins.
AXIN2 is a non‐redundant regulator of AXIN1 stability and β‐catenin in colorectal cancer cells
Conflict of interest The authors declare no conflict of interest. References 1 & (2018) Wnt signaling in development and tissue homeostasis. Development 145, dev146589. 2, , & (2019) An aggregon in conductin/axin2 regulates Wnt/beta-catenin signaling and holds potential for cancer therapy. Nat Commun 10, 4251. 3, , , , , , , , , et al. (2002) Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol Cell Biol 22, 1184–1193.
Complex IIa formation and ABC transporters determine sensitivity of OSCC to Smac mimetics - Cell Death & Disease
Abstract Small molecule inhibitors of apoptosis proteins (IAPs) antagonists, known as Smac mimetics (SMs), activate non-canonical NF-κB and sensitize cancer cells to TNF-induced cell death. SMs are currently in phase III clinical trials for head and neck squamous cell carcinoma (HNSCC) after promising phase II trials. To explore the utility of SMs in oral squamous cell carcinoma (OSCC), we tested nine human OSCC cell lines and correlated SM sensitivity with both IAP mutation and expression levels.
Correction to: RIPK1 prevents TRADD-driven, but TNFR1 independent, apoptosis during development - Cell Death & Differentiation
Correction to: Cell Death & Differentiation https://doi.org/10.1038/s41418-018-0166-8, published online 05 September 2018 In the published article “RIPK1 prevents TRADD-driven, but TNFR1 independent, apoptosis during development”, we would like to address an error identified in Figure 5B, skin panel. Specifically, the image representing Ripk1+/+; Tradd+/+ wildtype mice was unintentionally duplicated. This error occurred during the figure preparation process.
Spatial proteomics identifies JAKi as treatment for a lethal skin disease - Nature
Abstract Toxic epidermal necrolysis (TEN) is a fatal drug-induced skin reaction triggered by common medications and is an emerging public health issue1,2,3. Patients with TEN undergo severe and sudden epidermal detachment caused by keratinocyte cell death. Although molecular mechanisms that drive keratinocyte cell death have been proposed, the main drivers remain unknown, and there is no effective therapy for TEN4,5,6.
Intracellular zinc protects tumours from T cell-mediated cytotoxicity - Cell Death & Differentiation
Abstract Tumour immune evasion presents a significant challenge to the effectiveness of cancer immunotherapies. Recent advances in high-throughput screening techniques have uncovered that loss of antigen presentation and cytokine signalling pathways are central mechanisms by which tumours evade T cell immunity.
Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency - Nature Immunology
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Abstract The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN and is essential for proper immune responses. Individuals with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage disease. In mice, the loss of Sharpin leads to severe dermatitis due to excessive keratinocyte cell death.
By Hirotsugu Oda, Kalpana Manthiram, Pallavi Pimpale Chavan, Shuichiro Nakabo, Mariël Swart, Nisa Celik, Vahid Ziaee, Nasim Movahedi, Raphael Carapito, Qin Xu, David Beck, Natalie Deuitch, James C. Mullikin, Kerry Dobbs, Holly Anderton, Kate Lawlor, Hiroyuki Yoshitomi, Mariana J. Kaplan, Christian Mayer, Luigi D. Notarangelo, Kazuhiro Iwai, John Silke, Bertrand Boisson, Jean-Laurent Casanova Verified, Seiamak Bahram, Nieves Peltzer, Najoua Lalaoui, Ivona Aksentijevich
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Nature
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Blocking cell death limits lung damage and inflammation from influenza
NEWS AND VIEWS 10 April 2024 Animals that receive an inhibitor of an antiviral cell-death response called necroptosis are less likely to die of influenza even at a late stage of infection. This has implications for the development of therapies for respiratory diseases. If there is one lesson to be learnt from the pandemic, it is that we need to be better prepared for the next one. Influenza pandemics have killed millions in the past and could do so again.
RIPK1 and necroptosis role in premature ageing - Nature Cell Biology
Progeria, or premature ageing, is a devastating condition caused by defects in the nuclear envelope and is associated with systemic inflammation. A study now shows in animal models that inhibiting necroptosis, and particularly activity of the RIPK1 kinase, reduces inflammation and results in a meaningful extension in lifespan1.
RIPK3 cleavage is dispensable for necroptosis inhibition but restricts NLRP3 inflammasome activation - Cell Death & Differentiation
Abstract Caspase-8 activity is required to inhibit necroptosis during embryogenesis in mice. In vitro studies have suggested that caspase-8 directly cleaves RIPK1, CYLD and the key necroptotic effector kinase RIPK3 to repress necroptosis. However, recent studies have shown that mice expressing uncleavable RIPK1 die during embryogenesis due to excessive apoptosis, while uncleavable CYLD mice are viable. Therefore, these results raise important questions about the role of RIPK3 cleavage.
A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation - Nature Communications
Abstract Across the globe, 2-3% of humans carry the p.Ser132Pro single nucleotide polymorphism in MLKL, the terminal effector protein of the inflammatory form of programmed cell death, necroptosis. Here we show that this substitution confers a gain in necroptotic function in human cells, with more rapid accumulation of activated MLKLS132P in biological membranes and MLKLS132P overriding pharmacological and endogenous inhibition of MLKL.
High molecular weight hyaluronic acid drastically reduces chemotherapy-induced mucositis and apoptotic cell death - Cell Death & Disease
Abstract Oral and intestinal mucositis (OIM) are debilitating inflammatory diseases initiated by oxidative stress, resulting in epithelial cell death and are frequently observed in cancer patients undergoing chemo-radiotherapy. There are currently few preventative strategies for this debilitating condition. Therefore, the development of a safe and effective mucositis mitigating strategy is an unmet medical need. Hyaluronic acid (HA) preparations have been tentatively used in oral mucositis.
Deletion of Gpatch2 does not alter Tnf expression in mice - Cell Death & Disease
Abstract The cytokine TNF has essential roles in immune defence against diverse pathogens and, when its expression is deregulated, it can drive severe inflammatory disease. The control of TNF levels is therefore critical for normal functioning of the immune system and health. We have identified GPATCH2 as a putative repressor of Tnf expression acting post-transcriptionally through the TNF 3’ UTR in a CRISPR screen for novel regulators of TNF.
MLKL deficiency protects against low-grade, sterile inflammation in aged mice - Cell Death & Differentiation
Abstract MLKL and RIPK3 are the core signaling proteins of the inflammatory cell death pathway, necroptosis, which is a known mediator and modifier of human disease. Necroptosis has been implicated in the progression of disease in almost every physiological system and recent reports suggest a role for necroptosis in aging.
The unifying catalytic mechanism of the RING-between-RING E3 ubiquitin ligase family - Nature Communications
Plasmids The DNA sequences coding for full-length human HOIL-1 and mouse HECTD1 (amino acids 2106–2618), both optimized for expression in E. coli (gBlock Gene Fragment, IDT Singapore), were inserted into the pOPINB vector (Berrow et al. 50) using in-fusion cloning (Takara Bio). UBE1, RNF216, HOIP, UbcH7, native Ub and M1 di-Ub constructs were described previously6,23.
OXTRHigh stroma fibroblasts control the invasion pattern of oral squamous cell carcinoma via ERK5 signaling - Nature Communications
Abstract The Pattern Of Invasion (POI) of tumor cells into adjacent normal tissues clinically predicts postoperative tumor metastasis/recurrence of early oral squamous cell carcinoma (OSCC), but the mechanisms underlying the development of these subtypes remain unclear. Focusing on the highest score of POIs (Worst POI, WPOI) present within each tumor, we observe a disease progression-driven shift of WPOI towards the high-risk type 4/5, associated with a mesenchymal phenotype in advanced OSCC.
Cell death in chronic inflammation: breaking the cycle to treat rheumatic disease
Abstract Cell death is a vital process that occurs in billions of cells in the human body every day. This process helps maintain tissue homeostasis, supports recovery from acute injury, deals with infection and regulates immunity. Cell death can also provoke inflammatory responses, and lytic forms of cell death can incite inflammation. Loss of cell membrane integrity leads to the uncontrolled release of damage-associated molecular patterns (DAMPs), which are normally sequestered inside cells.
What is autoinflammatory disease? • The Medical Republic
Just over 20 years ago, people from three generations of an American family were referred to the National Institutes of Health (NIH) in Washington DC with an unknown disease. They were ten to 82 years old and had symptoms including monthly episodes of unexplained high fevers (up to 41?), lasting two to seven days. They also had painful swollen lymph nodes, enlarged spleens and livers, abdominal pain, mouth ulcers, joint pain, and a patchwork of other symptoms.
Autoinflammatory disease: The rare immune condition with waves of fever
Credit: www.shutterstock.com Just over 20 years ago, people from three generations of an American family were referred to the National Institutes of Health (NIH) in Washington DC with an unknown disease. They were ten to 82 years old and had symptoms including monthly episodes of unexplained high fevers (up to 41℃), lasting two to seven days. They also had painful swollen lymph nodes, enlarged spleens and livers, abdominal pain, mouth ulcers, joint pain, and a patchwork of other symptoms.
What is autoinflammatory disease, the rare immune condition with waves of fever?
Just over 20 years ago, people from three generations of an American family were referred to the National Institutes of Health (NIH) in Washington DC with an unknown disease. They were ten to 82 years old and had symptoms including monthly episodes of unexplained high fevers (up to 41℃), lasting two to seven days. They also had painful swollen lymph nodes, enlarged spleens and livers, abdominal pain, mouth ulcers, joint pain, and a patchwork of other symptoms.
The Walrus and the Carpenter: Complex Regulation of Tumor Immunity in Colorectal Cancer
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In lab study, Conatus' emricasan boosts leukemia drug's effectiveness
A drug in clinical trials for liver diseases by a San Diego biotech company may be useful in treating acute myeloid leukemia, according to research published this week.The drug, emricasan, was tested in combination with another drug also in testing, birinapant.
Killing Lymphoma with Smac-Mimetics: As Easy as ABC?
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