32 results on '"Silke, John"'
Search Results
2. Deletion of Gpatch2 does not alter Tnf expression in mice.
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Dalseno, Destiny, Anderton, Holly, Kueh, Andrew, Herold, Marco J, Silke, John, Strasser, Andreas, and Bouillet, Philippe
- Published
- 2023
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3. The unifying catalytic mechanism of the RING-between-RING E3 ubiquitin ligase family.
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Wang, Xiangyi S., Cotton, Thomas R., Trevelyan, Sarah J., Richardson, Lachlan W., Lee, Wei Ting, Silke, John, and Lechtenberg, Bernhard C.
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UBIQUITIN ligases ,UBIQUITIN-conjugating enzymes ,BINDING sites ,ALLOSTERIC regulation ,UBIQUITIN ,CATALYTIC activity - Abstract
The RING-between-RING (RBR) E3 ubiquitin ligase family in humans comprises 14 members and is defined by a two-step catalytic mechanism in which ubiquitin is first transferred from an E2 ubiquitin-conjugating enzyme to the RBR active site and then to the substrate. To define the core features of this catalytic mechanism, we here structurally and biochemically characterise the two RBRs HOIL-1 and RNF216. Crystal structures of both enzymes in their RBR/E2-Ub/Ub transthiolation complexes capturing the first catalytic step, together with complementary functional experiments, reveal the defining features of the RBR catalytic mechanism. RBRs catalyse ubiquitination via a conserved transthiolation complex structure that enables efficient E2-to-RBR ubiquitin transfer. Our data also highlight a conserved RBR allosteric activation mechanism by distinct ubiquitin linkages that suggests RBRs employ a feed-forward mechanism. We finally identify that the HOIL-1 RING2 domain contains an unusual Zn2/Cys6 binuclear cluster that is required for catalytic activity and substrate ubiquitination. RBR E3 ubiquitin ligases utilise a 2-step catalytic mechanism previously defined for only few of the RBR family members. Here, the authors examine the poorly studied RBRs HOIL-1 and RNF216 to define general principles of RBR catalysis and regulation and identify specific functional differences. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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4. Blocking cell death limits lung damage and inflammation from influenza.
- Author
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Gupta, Nishma and Silke, John
- Abstract
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.Inhibiting necroptosis protects lungs against influenza-mediated damage. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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5. OXTRHigh stroma fibroblasts control the invasion pattern of oral squamous cell carcinoma via ERK5 signaling.
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Ding, Liang, Fu, Yong, Zhu, Nisha, Zhao, Mengxiang, Ding, Zhuang, Zhang, Xiaoxin, Song, Yuxian, Jing, Yue, Zhang, Qian, Chen, Sheng, Huang, Xiaofeng, O'Reilly, Lorraine A, Silke, John, Hu, Qingang, and Ni, Yanhong
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EXTRACELLULAR signal-regulated kinases ,SQUAMOUS cell carcinoma ,FIBROBLASTS ,OXYTOCIN receptors ,CANCER invasiveness ,METASTASIS - 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. WPOI 4-5-derived cancer-associated fibroblasts (CAFs
WPOI4-5 ), characterized by high oxytocin receptor expression (OXTRHigh ), contribute to local-regional metastasis. OXTRHigh CAFs induce a desmoplastic stroma and CCL26 is required for the invasive phenotype of CCR3+ tumors. Mechanistically, OXTR activates nuclear ERK5 transcription signaling via Gαq and CDC37 to maintain high levels of OXTR and CCL26. ERK5 ablation reprograms the pro-invasive phenotype of OXTRHigh CAFs. Therefore, targeting ERK5 signaling in OXTRHigh CAFs is a potential therapeutic strategy for OSCC patients with WPOI 4-5. Worst pattern of invasion (WPOI) is a parameter used to quantify tumor invasiveness of oral squamous cell carcinoma (OSCC). Here the authors show that a fibroblast subset characterized by the expression of the oxytocin receptor is enriched in highly invasive WPOI 4-5 OSCC tumors and can be targeted to reduce the desmoplastic stroma and tumor metastasis. [ABSTRACT FROM AUTHOR]- Published
- 2022
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6. The Lck inhibitor, AMG-47a, blocks necroptosis and implicates RIPK1 in signalling downstream of MLKL.
- Author
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Jacobsen, Annette V., Pierotti, Catia L., Lowes, Kym N., Au, Amanda E., Zhang, Ying, Etemadi, Nima, Fitzgibbon, Cheree, Kersten, Wilhelmus J. A., Samson, André L., van Delft, Mark F., Huang, David C. S., Sabroux, Hélène Jousset, Lessene, Guillaume, Silke, John, and Murphy, James M.
- Published
- 2022
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7. The necroptotic cell death pathway operates in megakaryocytes, but not in platelet synthesis.
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Moujalled, Diane, Gangatirkar, Pradnya, Kauppi, Maria, Corbin, Jason, Lebois, Marion, Murphy, James M., Lalaoui, Najoua, Hildebrand, Joanne M., Silke, John, Alexander, Warren S., and Josefsson, Emma C.
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- 2021
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8. Transplantable programmed death ligand 1 expressing gastroids from gastric cancer prone Nfkb1−/− mice.
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Low, Jun T., Ho, Gwo-Yaw, Scott, Mark, Tan, Chin Wee, Whitehead, Lachlan, Barber, Kathy, Yip, Hon Y. K., Dekkers, Johanna F., Hirokawa, Yumiko, Silke, John, Burgess, Antony W., Strasser, Andreas, Putoczki, Tracy L., and O'Reilly, Lorraine A.
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- 2021
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9. MLKL trafficking and accumulation at the plasma membrane control the kinetics and threshold for necroptosis.
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Samson, Andre L., Zhang, Ying, Geoghegan, Niall D., Gavin, Xavier J., Davies, Katherine A., Mlodzianoski, Michael J., Whitehead, Lachlan W., Frank, Daniel, Garnish, Sarah E., Fitzgibbon, Cheree, Hempel, Anne, Young, Samuel N., Jacobsen, Annette V., Cawthorne, Wayne, Petrie, Emma J., Faux, Maree C., Shield-Artin, Kristy, Lalaoui, Najoua, Hildebrand, Joanne M., and Silke, John
- Subjects
CELL membranes ,CELL junctions ,PLASMA confinement ,TIGHT junctions ,MICROTUBULES ,CELL death ,ANALYTICAL mechanics - Abstract
Mixed lineage kinase domain-like (MLKL) is the terminal protein in the pro-inflammatory necroptotic cell death program. RIPK3-mediated phosphorylation is thought to initiate MLKL oligomerization, membrane translocation and membrane disruption, although the precise choreography of events is incompletely understood. Here, we use single-cell imaging approaches to map the chronology of endogenous human MLKL activation during necroptosis. During the effector phase of necroptosis, we observe that phosphorylated MLKL assembles into higher order species on presumed cytoplasmic necrosomes. Subsequently, MLKL co-traffics with tight junction proteins to the cell periphery via Golgi-microtubule-actin-dependent mechanisms. MLKL and tight junction proteins then steadily co-accumulate at the plasma membrane as heterogeneous micron-sized hotspots. Our studies identify MLKL trafficking and plasma membrane accumulation as crucial necroptosis checkpoints. Furthermore, the accumulation of phosphorylated MLKL at intercellular junctions accelerates necroptosis between neighbouring cells, which may be relevant to inflammatory bowel disease and other necroptosis-mediated enteropathies. Mixed lineage kinase domain-like (MLKL) is the terminal protein in the pro-inflammatory necroptotic cell death program. Here the authors show that MLKL trafficking and plasma membrane accumulation are crucial necroptosis checkpoints, and that accumulation of phosphorylated MLKL at intercellular junctions promotes necroptosis. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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10. Conformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis.
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Petrie, Emma J., Sandow, Jarrod J., Jacobsen, Annette V., Smith, Brian J., Griffin, Michael D. W., Lucet, Isabelle S., Weiwen Dai, Young, Samuel N., Tanzer, Maria C., Wardak, Ahmad, Lung-Yu Liang, Cowan, Angus D., Hildebrand, Joanne M., Kersten, Wilhelmus J. A., Lessene, Guillaume, Silke, John, Czabotar, Peter E., Webb, Andrew I., and Murphy, James M.
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CELL death ,MOLECULAR switches ,CELL membranes - Abstract
Necroptotic cell death is mediated by the most terminal known effector of the pathway, MLKL. Precisely how phosphorylation of the MLKL pseudokinase domain activation loop by the upstream kinase, RIPK3, induces unmasking of the N-terminal executioner four-helix bundle (4HB) domain of MLKL, higher-order assemblies, and permeabilization of plasma membranes remains poorly understood. Here, we reveal the existence of a basal monomeric MLKL conformer present in human cells prior to exposure to a necroptotic stimulus. Following activation, toggling within the MLKL pseudokinase domain promotes 4HB domain disengagement from the pseudokinase domain αC helix and pseudocatalytic loop, to enable formation of a necroptosis-inducing tetramer. In contrast to mouse MLKL, substitution of RIPK3 substrate sites in the human MLKL pseudokinase domain completely abrogated necroptotic signaling. Therefore, while the pseudokinase domains of mouse and human MLKL function as molecular switches to control MLKL activation, the underlying mechanism differs between species. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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11. The intersection of cell death and inflammasome activation.
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Vince, James and Silke, John
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INFLAMMASOMES , *CELL death , *NECROSIS , *INTERLEUKINS , *APOPTOSIS , *INFLAMMATION - Abstract
Inflammasomes sense cellular danger to activate the cysteine-aspartic protease caspase-1, which processes precursor interleukin-1β (IL-1β) and IL-18 into their mature bioactive fragments. In addition, activated caspase-1 or the related inflammatory caspase, caspase-11, can cleave gasdermin D to induce a lytic cell death, termed pyroptosis. The intertwining of IL-1β activation and cell death is further highlighted by research showing that the extrinsic apoptotic caspase, caspase-8, may, like caspase-1, directly process IL-1β, activate the NLRP3 inflammasome itself, or bind to inflammasome complexes to induce apoptotic cell death. Similarly, RIPK3- and MLKL-dependent necroptotic signaling can activate the NLRP3 inflammasome to drive IL-1β inflammatory responses in vivo. Here, we review the mechanisms by which cell death signaling activates inflammasomes to initiate IL-1β-driven inflammation, and highlight the clinical relevance of these findings to heritable autoinflammatory diseases. We also discuss whether the act of cell death can be separated from IL-1β secretion and evaluate studies suggesting that several cell death regulatory proteins can directly interact with, and modulate the function of, inflammasome and IL-1β containing protein complexes. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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12. IAPs and Necroptotic Cell Death.
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Silke, John and Vaux, David
- Abstract
The word ˵necroptosis″ refers to a mechanism for cell suicide that does not require caspase activity or the proapoptotic Bcl-2 family members Bax and Bak. It can be triggered following ligation of certain members of the TNF receptor superfamily that activate a pathway involving proteins such as the RIP kinases and the pseudokinase MLKL. Signalling by this pathway is modulated by other proteins, such as the TNF receptor-associated factors (TRAFs) and the inhibitor of apoptosis proteins (IAPs). cIAPs interact with TRAFs, ubiquitylate RIP kinases and thereby promote activation of canonical NF-κB by TNF receptors and regulate RIP kinase levels at signalling complexes. ˵Smac-mimetic″ compounds antagonise cIAPs to promote cell death by both caspase-dependent apoptotic and caspase-independent necroptotic mechanisms. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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13. The diverse role of RIP kinases in necroptosis and inflammation.
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Silke, John, Rickard, James A, and Gerlic, Motti
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INFLAMMATION , *KINASES , *CYTOKINES , *TUMOR necrosis factors , *CASPASES , *CELL death - Abstract
Inflammation is a healthy response to infection or danger and should be rapid, specific and terminated once the threat has passed. Inflammatory diseases, where this regulation fails, cause considerable human suffering. Treatments have successfully targeted pro-inflammatory cytokines, such as tumor-necrosis factor (TNF), that directly induce genes encoding inflammatory products. Inflammatory signals, including TNF, may also directly induce caspase-independent cell death (necroptosis), which can also elicit inflammation. Necroptosis was originally defined as being dependent on the kinase RIPK1 but is now known to be dependent on RIPK3 and the pseudo-kinase MLKL. Therefore, RIPK1, RIPK3 and MLKL are potential therapeutic targets. RIPK1 and RIPK3 also directly regulate inflammatory signaling, which complicates interpretation of their function but might alter their therapeutic utility. This Review examines the role of cell death, particularly necroptosis, in inflammation, in the context of recent insights into the roles of the key necroptosis effector molecules RIPK1, RIPK3 and MLKL. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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14. Workshop Summary: Novel Aspects of the Functions of the TRAFs and cIAPs.
- Author
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Silke, John and Vucic, Domagoj
- Abstract
Session 8 of TNF2009 focused on the function of the RING containing proteins TRAF2 and cIAPs in TNF signaling. TNF-R1 signaling is understood to be carefully balanced between a pro-survival and pro-apoptotic response and, as might be expected for proteins containing these E3 ligase domains, much of the data and discussion revolved around the regulation of these alternative pathways by ubiquitylation. The session was also notable for talks that extended dramatically our understanding of regulation of other signaling pathways by cIAPs such as necrosis and immune responses. Furthermore there was thought provoking data looking at the role of the RIP kinase family in TNF signaling and the role they play in non-apoptotic cell death pathways initiated by TNF. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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15. New Perspectives in TNF-R1-Induced NF-ΚB Signaling.
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Gentle, Ian E. and Silke, John
- Abstract
The ubiquitylation events leading to activation of NF-ΚB at the TNFR1 receptor have been a topic of intense study. It is believed that K63 ubiquitylation of the kinase RIPK1 is required for recruitment of the TAB2/TAB3/TAK1 and IKK1/IKK2/NEMO complexes that are in turn required to phosphorylate and degrade IΚBα allowing freed NF-ΚB dimers to nuclear translocation. The exact involvement of the E3 ligases, TRAF2, TRAF5, cIAP1, and cIAP2 in this process has been unclear. We summarize a recent study from our lab defining the roles of TRAF2 and cIAP1 s in activation of NF-ΚB downstream of TNF-R1 and report the surprising finding that RIPK1 is not essential for TNF-R1-induced NF-ΚB. Alternative mechanisms of how NF-ΚB may be activated by TNF-R1 in the light of these findings are discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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16. Inhibitor of Apoptosis Proteins and Caspases.
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Srivastava, Rakesh, Yu, Jai Y., Silke, John, and Ekert, Paul G.
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Inhibitors of apoptosis proteins (IAPs) were first identified as insect viral proteins that block host cell apoptosis. Cellular homologs bearing the characteristic baculoviral IAP repeat (BIR) domain have now been found in all metazoans and have more diverse functions than their name suggests. Some cellular IAPs do, in fact, inhibit apoptosis, in part at least by directly inhibiting cysteine proteases, called caspases, that are ultimately responsible for killing a cell. The primary aim of this chapter is to explore the intricate regulation of caspases by IAPs, and the exquisite counter regulation of IAPs by antagonist proteins. Interest in IAPs extends beyond apoptosis pathways and recent evidence suggests that IAPs modulate cell-signaling pathways that affect growth and proliferation and some of these remarkable studies will be discussed. [ABSTRACT FROM AUTHOR]
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- 2007
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17. Linear ubiquitination prevents inflammation and regulates immune signalling.
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Gerlach, Björn, Cordier, Stefanie M., Schmukle, Anna C., Emmerich, Christoph H., Rieser, Eva, Haas, Tobias L., Webb, Andrew I., Rickard, James A., Anderton, Holly, Wong, Wendy W.-L., Nachbur, Ueli, Gangoda, Lahiru, Warnken, Uwe, Purcell, Anthony W., Silke, John, and Walczak, Henning
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TUMOR necrosis factors ,SKIN inflammation ,MASS spectrometry ,CYTOKINES ,GLYCOPROTEINS - Abstract
Members of the tumour necrosis factor (TNF) receptor superfamily have important functions in immunity and inflammation. Recently linear ubiquitin chains assembled by a complex containing HOIL-1 and HOIP (also known as RBCK1 and RNF31, respectively) were implicated in TNF signalling, yet their relevance in vivo remained uncertain. Here we identify SHARPIN as a third component of the linear ubiquitin chain assembly complex, recruited to the CD40 and TNF receptor signalling complexes together with its other constituents, HOIL-1 and HOIP. Mass spectrometry of TNF signalling complexes revealed RIP1 (also known as RIPK1) and NEMO (also known as IKKγ or IKBKG) to be linearly ubiquitinated. Mutation of the Sharpin gene (Sharpin
cpdm/cpdm ) causes chronic proliferative dermatitis (cpdm) characterized by inflammatory skin lesions and defective lymphoid organogenesis. Gene induction by TNF, CD40 ligand and interleukin-1β was attenuated in cpdm-derived cells which were rendered sensitive to TNF-induced death. Importantly, Tnf gene deficiency prevented skin lesions in cpdm mice. We conclude that by enabling linear ubiquitination in the TNF receptor signalling complex, SHARPIN interferes with TNF-induced cell death and, thereby, prevents inflammation. Our results provide evidence for the relevance of linear ubiquitination in vivo in preventing inflammation and regulating immune signalling. [ABSTRACT FROM AUTHOR]- Published
- 2011
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18. XIAP discriminates between type I and type II FAS-induced apoptosis.
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Jost, Philipp J., Grabow, Stephanie, Gray, Daniel, McKenzie, Mark D., Nachbur, Ueli, Huang, David C. S., Bouillet, Philippe, Thomas, Helen E., Borner, Christoph, Silke, John, Strasser, Andreas, and Kaufmann, Thomas
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APOPTOSIS ,RECEPTOR-ligand complexes ,DNA-ligand interactions ,AUTOIMMUNITY ,LIVER cells ,AUTOANTIBODIES ,CARRIER proteins ,CANCER patients ,MOUSE diseases ,LABORATORY mice - Abstract
FAS (also called APO-1 and CD95) and its physiological ligand, FASL, regulate apoptosis of unwanted or dangerous cells, functioning as a guardian against autoimmunity and cancer development. Distinct cell types differ in the mechanisms by which the ‘death receptor’ FAS triggers their apoptosis. In type I cells, such as lymphocytes, activation of ‘effector caspases’ by FAS-induced activation of caspase-8 suffices for cell killing, whereas in type II cells, including hepatocytes and pancreatic β-cells, caspase cascade amplification through caspase-8-mediated activation of the pro-apoptotic BCL-2 family member BID (BH3 interacting domain death agonist) is essential. Here we show that loss of XIAP (X-chromosome linked inhibitor of apoptosis protein) function by gene targeting or treatment with a second mitochondria-derived activator of caspases (SMAC, also called DIABLO; direct IAP-binding protein with low pI) mimetic drug in mice rendered hepatocytes and β-cells independent of BID for FAS-induced apoptosis. These results show that XIAP is the critical discriminator between type I and type II apoptosis signalling and suggest that IAP inhibitors should be used with caution in cancer patients with underlying liver conditions. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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19. IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-κB as well as cell survival and oncogenesis.
- Author
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Gyrd-Hansen, Mads, Darding, Maurice, Miasari, Maria, Santoro, Massimo M., Zender, Lars, Xue, Wen, Tenev, Tencho, da Fonseca, Paula C.A., Zvelebil, Marketa, Bujnicki, Janusz M., Lowe, Scott, Silke, John, and Meier, Pascal
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UBIQUITIN ,DNA repair ,CARCINOGENESIS ,TUMOR growth ,BIOCHEMICAL genetics ,PROTEINS - Abstract
The covalent attachment of ubiquitin to target proteins influences various cellular processes, including DNA repair, NF-κB signalling and cell survival. The most common mode of regulation by ubiquitin-conjugation involves specialized ubiquitin-binding proteins that bind to ubiquitylated proteins and link them to downstream biochemical processes. Unravelling how the ubiquitin-message is recognized is essential because aberrant ubiquitin-mediated signalling contributes to tumour formation. Recent evidence indicates that inhibitor of apoptosis (IAP) proteins are frequently overexpressed in cancer and their expression level is implicated in contributing to tumorigenesis, chemoresistance, disease progression and poor patient-survival. Here, we have identified an evolutionarily conserved ubiquitin-associated (UBA) domain in IAPs, which enables them to bind to Lys 63-linked polyubiquitin. We found that the UBA domain is essential for the oncogenic potential of cIAP1, to maintain endothelial cell survival and to protect cells from TNF-α-induced apoptosis. Moreover, the UBA domain is required for XIAP and cIAP2–MALT1 to activate NF-κB. Our data suggest that the UBA domain of cIAP2–MALT1 stimulates NF-κB signalling by binding to polyubiquitylated NEMO. Significantly, 98% of all cIAP2–MALT1 fusion proteins retain the UBA domain, suggesting that ubiquitin-binding contributes to the oncogenic potential of cIAP2–MALT1 in MALT lymphoma. Our data identify IAPs as ubiquitin-binding proteins that contribute to ubiquitin-mediated cell survival, NF-κB signalling and oncogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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20. IAPs, RINGs and ubiquitylation.
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Vaux, David L. and Silke, John
- Subjects
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APOPTOSIS , *PROTEINS , *UBIQUITIN , *ENZYMES , *BACULOVIRUSES - Abstract
The inhibitor of apoptosis (IAP) proteins all contain one or more baculoviral IAP repeat motifs, through which they interact with various other proteins. Many IAPs also have another zinc-binding motif, the RING domain, which can recruit E2 ubiquitin-conjugating enzymes and catalyse the transfer of ubiquitin onto target proteins. The number of targets of IAP-mediated ubiquitylation is increasing and recent results indicate that outcomes following ubiquitylation are tantalizingly complex. As well as regulating other proteins, the IAPs themselves are controlled by ubiquitin-mediated degradation. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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21. Programmed cell death: Superman meets Dr Death.
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Meier, Pascal and Silke, John
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CONFERENCE proceedings (Publications) , *CELL death , *APOPTOSIS , *HOMEOSTASIS , *GLUCOSE , *LIPID metabolism , *CELL proliferation , *CELL differentiation - Abstract
This year's Cold Spring Harbor meeting on programmed cell death (September 17-21, 2003), organised by Craig Thompson and Junying Yuan, was proof that the 'golden age' of research in this field is far from over. There was a flurry of fascinating insights into the regulation of diverse apoptotic pathways and unexpected non-apoptotic roles for some of the key apoptotic regulators and effectors. In addition to their role in cell death, components of the apoptotic molecular machinery are now known to also function in a variety of essential cellular processes, such as regulating glucose homeostasis, lipid metabolism, cell proliferation and differentiation. [ABSTRACT FROM AUTHOR]
- Published
- 2003
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22. Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome.
- Author
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Marsden, Vanessa S., O'Connor, Liam, O'Reilly, Lorraine A., Silke, John, Metcalf, Donald, Ekert, Paul G., Huang, David C. S., Cecconi, Francesco, Kuida, Keisuke, Tomaselli, Kevin J., Roy, Sophie, Nicholson, Don W., Vaux, David L., Bouillet, Philippe, Adams, Jerry M., and Strasser, Andreas
- Subjects
APOPTOSIS ,CYSTEINE proteinases ,CAENORHABDITIS elegans ,HEMATOPOIESIS - Abstract
Apoptosis is an evolutionarily conserved cell suicide process executed by cysteine proteases (caspases) and regulated by the opposing factions of the Bcl-2 protein family. Mammalian caspase-9 and its activator Apaf-1 were thought to be essential, because mice lacking either of them display neuronal hyperplasia and their lymphocytes and fibroblasts seem resistant to certain apoptotic stimuli. Because Apaf-1 requires cytochrome c to activate caspase-9, and Bcl-2 prevents mitochondrial cytochrome c release, Bcl-2 is widely believed to inhibit apoptosis by safeguarding mitochondrial membrane integrity. Our results suggest a different, broader role, because Bcl-2 overexpression increased lymphocyte numbers in mice and inhibited many apoptotic stimuli, but the absence of Apaf-1 or caspase-9 did not. Caspase activity was still discernible in cells lacking Apaf-1 or caspase-9, and a potent caspase antagonist both inhibited apoptosis and retarded cytochrome c release. We conclude that Bcl-2 regulates a caspase activation programme independently of the cytochrome c/Apaf-1/caspase-9 ‘apoptosome’, which seems to amplify rather than initiate the caspase cascade. [ABSTRACT FROM AUTHOR]
- Published
- 2002
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23. Evidence for erosion of mouse CpG islands during mammalian evolution.
- Author
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Matsuo, Koichi, Clay, Oliver, Takahashi, Takuya, Silke, John, and Schaffner, Walter
- Published
- 1993
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24. Is SIRT2 required for necroptosis?
- Author
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Newton, Kim, Hildebrand, Joanne M., Shen, Zhirong, Rodriguez, Diego, Alvarez-Diaz, Silvia, Petersen, Sean, Shah, Saumil, Dugger, Debra L., Huang, Chunzi, Auwerx, Johan, Vandenabeele, Peter, Green, Douglas R., Ashkenazi, Avi, Dixit, Vishva M., Kaiser, William J., Strasser, Andreas, Degterev, Alexei, and Silke, John
- Subjects
TUMORS ,NECROSIS ,CELL death ,PATHOLOGY ,GANGRENE - Abstract
Arising from N. Narayan et al. 492, 199-204 (2012)Sirtuins can promote deacetylation of a wide range of substrates in diverse cellular compartments to regulate many cellular processes; recently, Narayan et al. reported that SIRT2 was required for necroptosis on the basis of their findings that SIRT2 inhibition, knockdown or knockout prevented necroptosis. We sought to confirm and explore the role of SIRT2 in necroptosis and tested four different sources of the SIRT2 inhibitor AGK2, three independent short interfering RNAs (siRNAs) against Sirt2, and cells from two independently generated Sirt2
−/− mouse strains; however, we were unable to show that inhibiting or depleting SIRT2 protected cells from necroptosis. Furthermore, Sirt2−/− mice succumbed to tumour-necrosis factor (TNF)-induced systemic inflammatory response syndrome (SIRS) more rapidly than wild-type mice, whereas Ripk3−/− mice were resistant. Our results therefore question the importance of SIRT2 in the necroptosis cell death pathway. [ABSTRACT FROM AUTHOR]- Published
- 2014
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25. Is BID required for NOD signalling?
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Nachbur, Ueli, Vince, James E., O'Reilly, Lorraine A., Strasser, Andreas, and Silke, John
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OLIGOMERIZATION ,LABORATORY mice ,EXTRACELLULAR signal-regulated kinases ,GRAM-negative bacteria ,PEPTIDOGLYCANS - Abstract
Arising from G. Yeretssian et al. 474, 96-99 (2011).Innate immune signalling mediated by the nucleotide-binding and oligomerization domain (NOD) receptors for pathogen-associated constituents regulates the response to intracellular peptidoglycans present in Gram-negative and Gram-positive bacteria. Recently, Yeretssian et al. reported that the pro-apoptotic BH3-only BCL2 family member BID is essential for NOD-mediated immune signalling. This was on the basis of their finding that bone marrow-derived macrophages (BMDMs) from Bid
?/? mice failed to activate NF-?B and extracellular signal-regulated kinase (ERK), and were unable to secrete inflammatory cytokines after stimulation with NOD ligands, and that BID-deficient mice were also defective in mounting a cytokine response to in vivo challenge with NOD ligands. Using the same strain of Bid?/? mice used by Yeretssian et al., we found that the mice responded like wild-type mice to NOD ligands, and that the levels of NF-?B or ERK activation and cytokine secretion from Bid?/? BMDMs were indistinguishable from the wild-type response. We therefore propose that the non-apoptotic role of BID in inflammation and innate immunity should be reassessed. [ABSTRACT FROM AUTHOR]- Published
- 2012
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26. Addendum: A FRET biosensor for necroptosis uncovers two different modes of the release of DAMPs.
- Author
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Murai, Shin, Yamaguchi, Yoshifumi, Shirasaki, Yoshitaka, Yamagishi, Mai, Shindo, Ryodai, Hildebrand, Joanne M., Miura, Ryosuke, Nakabayashi, Osamu, Totsuka, Mamoru, Tomida, Taichiro, Adachi-Akahane, Satomi, Uemura, Sotaro, Silke, John, Yagita, Hideo, Miura, Masayuki, and Nakano, Hiroyasu
- Abstract
The cDNA sequence of human SMART described in this Article was misreported, as described in the accompanying Addendum. This error does not affect the results or any conclusion of the Article. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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27. A FRET biosensor for necroptosis uncovers two different modes of the release of DAMPs.
- Author
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Murai, Shin, Yamaguchi, Yoshifumi, Shirasaki, Yoshitaka, Yamagishi, Mai, Shindo, Ryodai, Hildebrand, Joanne M., Miura, Ryosuke, Nakabayashi, Osamu, Totsuka, Mamoru, Tomida, Taichiro, Adachi-Akahane, Satomi, Uemura, Sotaro, Silke, John, Yagita, Hideo, Miura, Masayuki, and Nakano, Hiroyasu
- Abstract
Necroptosis is a regulated form of necrosis that depends on receptor-interacting protein kinase (RIPK)3 and mixed lineage kinase domain-like (MLKL). While danger-associated molecular pattern (DAMP)s are involved in various pathological conditions and released from dead cells, the underlying mechanisms are not fully understood. Here we develop a fluorescence resonance energy transfer (FRET) biosensor, termed SMART (a sensor for MLKL activation by RIPK3 based on FRET). SMART is composed of a fragment of MLKL and monitors necroptosis, but not apoptosis or necrosis. Mechanistically, SMART monitors plasma membrane translocation of oligomerized MLKL, which is induced by RIPK3 or mutational activation. SMART in combination with imaging of the release of nuclear DAMPs and Live-Cell Imaging for Secretion activity (LCI-S) reveals two different modes of the release of High Mobility Group Box 1 from necroptotic cells. Thus, SMART and LCI-S uncover novel regulation of the release of DAMPs during necroptosis. Necroptotic cells activate MLKL and release inflammatory DAMPs, although the underlying regulatory mechanisms of this process are poorly understood. Here, Murai et al. develop a necroptosis-specific FRET sensor (SMART) that monitors MLKL membrane translocation to identify two modes of DAMP release. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
28. LUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L.
- Author
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Taraborrelli, Lucia, Peltzer, Nieves, Montinaro, Antonella, Kupka, Sebastian, Rieser, Eva, Hartwig, Torsten, Sarr, Aida, Darding, Maurice, Draber, Peter, Haas, Tobias L., Akarca, Ayse, Marafioti, Teresa, Pasparakis, Manolis, Bertin, John, Gough, Peter J., Bouillet, Philippe, Strasser, Andreas, Leverkus, Martin, Silke, John, and Walczak, Henning
- Abstract
The linear ubiquitin chain assembly complex (LUBAC), composed of HOIP, HOIL-1 and SHARPIN, is required for optimal TNF-mediated gene activation and to prevent cell death induced by TNF. Here, we demonstrate that keratinocyte-specific deletion of HOIP or HOIL-1 (E-KO) results in severe dermatitis causing postnatal lethality. We provide genetic and pharmacological evidence that the postnatal lethal dermatitis in Hoip
E-KO and Hoil-1E-KO mice is caused by TNFR1-induced, caspase-8-mediated apoptosis that occurs independently of the kinase activity of RIPK1. In the absence of TNFR1, however, dermatitis develops in adulthood, triggered by RIPK1-kinase-activity-dependent apoptosis and necroptosis. Strikingly, TRAIL or CD95L can redundantly induce this disease-causing cell death, as combined loss of their respective receptors is required to prevent TNFR1-independent dermatitis. These findings may have implications for the treatment of patients with mutations that perturb linear ubiquitination and potentially also for patients with inflammation-associated disorders that are refractory to inhibition of TNF alone. TNF mediated inflammation is critical in autoimmune mediated pathology, however many patients are refractory to current anti-TNF therapeutics. Here the authors show induction of several death ligands, in addition to TNF is sufficient to cause fatal dermatitis in a LUBAC deficient murine model of disease. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
29. Cell death in chronic inflammation: breaking the cycle to treat rheumatic disease.
- Author
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Anderton, Holly, Wicks, Ian P., and Silke, John
- Subjects
- *
CELL death , *RHEUMATISM , *APOPTOSIS , *INFLAMMATION , *BLEPHAROPTOSIS , *CELL physiology - 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. Such DAMPs increase local inflammation and promote the production of cytokines and chemokines that modulate the innate immune response. Cell death can be both a consequence and a cause of inflammation, which can be difficult to distinguish in chronic diseases. Despite this caveat, excessive or poorly regulated cell death is increasingly recognized as a contributor to chronic inflammation in rheumatic disease and other inflammatory conditions. Drugs that inhibit cell death could, therefore, be used therapeutically for the treatment of these diseases, and programmes to develop such inhibitors are already underway. In this Review, we outline pathways for the major cell death programmes (apoptosis, necroptosis, pyroptosis and NETosis) and their potential roles in chronic inflammation. We also discuss current and developing therapies that target the cell death machinery. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
30. Linear ubiquitin chain assembly complex coordinates late thymic T-cell differentiation and regulatory T-cell homeostasis.
- Author
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Teh, Charis E., Lalaoui, Najoua, Jain, Reema, Policheni, Antonia N., Heinlein, Melanie, Alvarez-Diaz, Silvia, Sheridan, Julie M., Rieser, Eva, Deuser, Stefanie, Darding, Maurice, Koay, Hui-Fern, Hu, Yifang, Kupresanin, Fiona, O'Reilly, Lorraine A., Godfrey, Dale I., Smyth, Gordon K., Bouillet, Philippe, Strasser, Andreas, Walczak, Henning, and Silke, John
- Published
- 2016
- Full Text
- View/download PDF
31. Erratum: The diverse role of RIP kinases in necroptosis and inflammation.
- Author
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Silke, John, Rickard, James A, and Gerlic, Motti
- Subjects
- *
PUBLISHED errata , *RECEPTOR-interacting proteins , *PROTEIN kinases , *INFLAMMATION , *NECROSIS , *MEDICAL publishing - Published
- 2015
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32. RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL.
- Author
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Lawlor, Kate E., Khan, Nufail, Mildenhall, Alison, Gerlic, Motti, Croker, Ben A., D'Cruz, Akshay A., Hall, Cathrine, Kaur Spall, Sukhdeep, Anderton, Holly, Masters, Seth L., Rashidi, Maryam, Wicks, Ian P., Alexander, Warren S., Mitsuuchi, Yasuhiro, Benetatos, Christopher A., Condon, Stephen M., Wong, W. Wei-Lynn, Silke, John, Vaux, David L., and Vince, James E.
- Published
- 2015
- Full Text
- View/download PDF
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