8 results on '"Chen, Kaiwen W"'
Search Results
2. Inflammasome and gasdermin signaling in neutrophils.
- Author
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Yow, See Jie, Yeap, Hui Wen, and Chen, Kaiwen W.
- Subjects
INFLAMMASOMES ,CELL death ,NEUTROPHILS ,PHAGOCYTES ,CELL communication ,PYROPTOSIS ,YERSINIA - Abstract
Inflammasomes and gasdermins mount potent host defense pathways against invading microbial pathogens, however, dysregulation in these pathways can drive a variety of inflammatory disorders. Neutrophils, historically regarded as effector phagocytes that drive host defense via microbial killing, are now emerging as critical drivers of immunity in vivo. Here, we summarize, the latest advancement in inflammasome, gasdermin, and cell death signaling in neutrophils. We discuss the mechanisms by which neutrophils resist caspase‐1‐dependent pyroptosis, the lytic function of gasdermin D and E during NETosis and Yersinia infection, and the contribution of neutrophil inflammasomes to inflammatory disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
3. Human GBP1 binds LPS to initiate assembly of a caspase-4 activating platform on cytosolic bacteria
- Author
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Santos, José Carlos, Boucher, Dave, Schneider, Larisa Kapinos, Demarco, Benjamin, Dilucca, Marisa, Shkarina, Kateryna, Heilig, Rosalie, Chen, Kaiwen W., Lim, Roderick Y. H., and Broz, Petr
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Lipopolysaccharides ,Pattern recognition receptors ,Inflammasomes ,Science ,Static Electricity ,Article ,Cell Line ,Inflammasome ,Cytosol ,GTP-Binding Proteins ,Salmonella ,Pyroptosis ,Humans ,lcsh:Science ,Innate immunity ,Intracellular Signaling Peptides and Proteins ,Epithelial Cells ,Phosphate-Binding Proteins ,Caspases, Initiator ,Enzyme Activation ,lcsh:Q ,lipids (amino acids, peptides, and proteins) ,Infection ,HeLa Cells ,Protein Binding - Abstract
The human non-canonical inflammasome controls caspase-4 activation and gasdermin-D-dependent pyroptosis in response to cytosolic bacterial lipopolysaccharide (LPS). Since LPS binds and oligomerizes caspase-4, the pathway is thought to proceed without dedicated LPS sensors or an activation platform. Here we report that interferon-induced guanylate-binding proteins (GBPs) are required for non-canonical inflammasome activation by cytosolic Salmonella or upon cytosolic delivery of LPS. GBP1 associates with the surface of cytosolic Salmonella seconds after bacterial escape from their vacuole, initiating the recruitment of GBP2-4 to assemble a GBP coat. The GBP coat then promotes the recruitment of caspase-4 to the bacterial surface and caspase activation, in absence of bacteriolysis. Mechanistically, GBP1 binds LPS with high affinity through electrostatic interactions. Our findings indicate that in human epithelial cells GBP1 acts as a cytosolic LPS sensor and assembles a platform for caspase-4 recruitment and activation at LPS-containing membranes as the first step of non-canonical inflammasome signaling., Detection of LPS derived from Gram-negative bacteria by innate immune receptors is a critical step in the host response. Here Santos and colleagues show human GBP1 binds to LPS resulting in non-canonical inflammasome activation.
- Published
- 2020
4. Interleukin-1β Maturation Triggers Its Relocation to the Plasma Membrane for Gasdermin-D-Dependent and -Independent Secretion.
- Author
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Monteleone, Mercedes, Stanley, Amanda C., Chen, Kaiwen W., Brown, Darren L., Bezbradica, Jelena S., von Pein, Jessica B., Holley, Caroline L., Boucher, Dave, Shakespear, Melanie R., Kapetanovic, Ronan, Rolfes, Verena, Sweet, Matthew J., Stow, Jennifer L., and Schroder, Kate
- Abstract
Summary IL-1β requires processing by caspase-1 to generate the active, pro-inflammatory cytokine. Acute IL-1β secretion from inflammasome-activated macrophages requires caspase-1-dependent GSDMD cleavage, which also induces pyroptosis. Mechanisms of IL-1β secretion by pyroptotic and non-pyroptotic cells, and the precise functions of caspase-1 and GSDMD therein, are unresolved. Here, we show that, while efficient early secretion of endogenous IL-1β from primary non-pyroptotic myeloid cells in vitro requires GSDMD, later IL-1β release in vitro and in vivo proceeds independently of GSDMD. IL-1β maturation is sufficient for slow, caspase-1/GSDMD-independent secretion of ectopic IL-1β from resting, non-pyroptotic macrophages, but the speed of IL-1β release is boosted by inflammasome activation, via caspase-1 and GSDMD. IL-1β cleavage induces IL-1β enrichment at PIP2-enriched plasma membrane ruffles, and this is a prerequisite for IL-1β secretion and is mediated by a polybasic motif within the cytokine. We thus reveal a mechanism in which maturation-induced IL-1β trafficking facilitates its unconventional secretion. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
5. Beyond inflammasomes: emerging function of gasdermins during apoptosis and NETosis.
- Author
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Chen, Kaiwen W, Demarco, Benjamin, and Broz, Petr
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APOPTOSIS , *INFLAMMASOMES , *PROTEINS , *CELLULAR signal transduction , *NECROSIS - Abstract
Programmed cell death is a key mechanism involved in several biological processes ranging from development and homeostasis to immunity, where it promotes the removal of stressed, damaged, malignant or infected cells. Abnormalities in the pathways leading to initiation of cell death or removal of dead cells are consequently associated with a range of human diseases including infections, autoinflammatory disease, neurodegenerative disease and cancer. Apoptosis, pyroptosis and NETosis are three well‐studied modes of cell death that were traditionally believed to be independent of one another, but emerging evidence indicates that there is extensive cross‐talk between them, and that all three pathways can converge onto the activation of the same cell death effector—the pore‐forming protein Gasdermin D (GSDMD). In this review, we highlight recent advances in gasdermin research, with a particular focus on the role of gasdermins in pyroptosis, NETosis and apoptosis, as well as cell type‐specific consequences of gasdermin activation. In addition, we discuss controversies surrounding a related gasdermin family protein, Gasdermin E (GSDME), in mediating pyroptosis and secondary necrosis following apoptosis, chemotherapy and inflammasome activation. [ABSTRACT FROM AUTHOR]
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- 2020
- Full Text
- View/download PDF
6. XIAP Loss Triggers RIPK3- and Caspase-8-Driven IL-1β Activation and Cell Death as a Consequence of TLR-MyD88-Induced cIAP1-TRAF2 Degradation
- Author
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Philipp J. Jost, Angelina J. Vince, Stephanie A. Conos, Yifan Zhan, Kate Schroder, David L. Vaux, Simon M Chatfield, Monica Yabal, Carina Graß, Stephanie Ziehe, John Silke, Kaiwen W. Chen, Kate E. Lawlor, Ken C Pang, Tan A. Nguyen, James E Vince, Damian B D'Silva, Rebecca Feltham, Cathrine Hall, Lawlor, Kate E, Feltham, Rebecca, Yabal, Monica, Conos, Stephanie A, Chen, Kaiwen W, Ziehe, Stephanie, Graß, Carina, Zhan, Yifan, Nguyen, Tan A, Hall, Cathrine, Vince, Angelina J, Chatfield, Simon M, D'Silva, Damian B, Pang, Kenneth C, Schroder, Kate, Silke, John, Vaux, David L, Jost, Philipp J, and Vince, James E
- Subjects
0301 basic medicine ,Programmed cell death ,TRAF2 ,proteasomal degradation ,Necroptosis ,Interleukin-1beta ,necroptosis ,Inhibitor of apoptosis ,Caspase 8 ,RIPK3 ,General Biochemistry, Genetics and Molecular Biology ,caspase-8 ,Inhibitor of Apoptosis Proteins ,03 medical and health sciences ,Mice ,XIAP ,NLRP3 ,autoinflammatory disease ,autoinflammatory conditions ,Toll-like receptor ,medicine ,XIAP deficiency ,Animals ,XIAP Deficiency ,lcsh:QH301-705.5 ,Mice, Knockout ,Cell Death ,Chemistry ,Toll-Like Receptors ,apoptosis ,Inflammasome ,interferon ,TNF Receptor-Associated Factor 2 ,3. Good health ,cIAP1 ,TNFR2 ,030104 developmental biology ,cell death ,interleukin (IL)-18 ,lcsh:Biology (General) ,Receptor-Interacting Protein Serine-Threonine Kinases ,Myeloid Differentiation Factor 88 ,Proteolysis ,Cancer research ,medicine.drug - Abstract
X-linked Inhibitor of Apoptosis (XIAP) deficiency predisposes people to pathogen-associated hyperinflammation. Upon XIAP loss, Toll-like receptor (TLR) ligation triggers RIPK3-caspase-8-mediated IL-1β activation and death in myeloid cells. How XIAP suppresses these events remains unclear. Here, we show that TLR-MyD88 causes the proteasomal degradation of the related IAP, cIAP1, and its adaptor, TRAF2, by inducing TNF and TNF Receptor 2 (TNFR2) signaling. Genetically, we define that myeloid-specific cIAP1 loss promotes TLR-induced RIPK3-caspase-8 and IL-1β activity in the absence of XIAP. Importantly, deletion of TNFR2 in XIAP-deficient cells limited TLR-MyD88-induced cIAP1-TRAF2 degradation, cell death, and IL-1β activation. In contrast to TLR-MyD88, TLR-TRIF-induced interferon (IFN)β inhibited cIAP1 loss and consequent cell death. These data reveal how, upon XIAP deficiency, a TLR-TNF-TNFR2 axis drives cIAP1-TRAF2 degradation to allow TLR or TNFR1 activation of RIPK3-caspase-8 and IL-1β. This mechanism may explain why XIAP-deficient patients can exhibit symptoms reminiscent of patients with activating inflammasome mutations. Refereed/Peer-reviewed
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- 2017
7. Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity
- Author
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Dave Boucher, Rebecca C. Coll, Alpha S. Yap, Damien Bierschenk, Jelena S. Bezbradica, Kaiwen W. Chen, Guillermo A. Gomez, Mercedes Monteleone, Kate Schroder, Katryn J. Stacey, Connie M. Ross, Jessica L. Teo, Caroline L. Holley, Boucher, Dave, Monteleone, Mercedes, Coll, Rebecca C, Chen, Kaiwen W, Ross, Connie M, Teo, Jessica L, Gomez, Guillermo A, Holley, Caroline L, Bierschenk, Damien, Stacey, Katryn J, Yap, Alpha S, Bezbradica, Jelena S, and Schroder, Kate
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0301 basic medicine ,Cell type ,Inflammasomes ,medicine.medical_treatment ,animal diseases ,viruses ,Immunology ,Kinetics ,Cell ,Interleukin-1beta ,Caspase 1 ,caspase-1 ,inflammasome-dependent inflammatory responses ,Article ,law.invention ,03 medical and health sciences ,Tetramer ,law ,medicine ,otorhinolaryngologic diseases ,Immunology and Allergy ,inflammasomes ,Research Articles ,Protease ,Chemistry ,Macrophages ,Inflammasome ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Recombinant DNA ,sense organs ,medicine.drug - Abstract
The inflammasome generates caspase-1 p20/p10, presumed to be the active protease. Boucher et al. demonstrate that the inflammasome contains an active caspase-1 species, p33/p10, and functions as a holoenzyme. Further caspase-1 self-processing generates and releases p20/p10 to terminate protease activity., Host-protective caspase-1 activity must be tightly regulated to prevent pathology, but mechanisms controlling the duration of cellular caspase-1 activity are unknown. Caspase-1 is activated on inflammasomes, signaling platforms that facilitate caspase-1 dimerization and autoprocessing. Previous studies with recombinant protein identified a caspase-1 tetramer composed of two p20 and two p10 subunits (p20/p10) as an active species. In this study, we report that in the cell, the dominant species of active caspase-1 dimers elicited by inflammasomes are in fact full-length p46 and a transient species, p33/p10. Further p33/p10 autoprocessing occurs with kinetics specified by inflammasome size and cell type, and this releases p20/p10 from the inflammasome, whereupon the tetramer becomes unstable in cells and protease activity is terminated. The inflammasome–caspase-1 complex thus functions as a holoenzyme that directs the location of caspase-1 activity but also incorporates an intrinsic self-limiting mechanism that ensures timely caspase-1 deactivation. This intrinsic mechanism of inflammasome signal shutdown offers a molecular basis for the transient nature, and coordinated timing, of inflammasome-dependent inflammatory responses., Graphical Abstract
- Published
- 2018
8. Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner
- Author
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James M. Murphy, Lachlan Whitehead, Lisa M Lindqvist, Seth L. Masters, Stephanie A. Conos, Dominic De Nardo, Hideki Hara, Kate Schroder, James E Vince, Gabriel Núñez, Kate E. Lawlor, David L. Vaux, Kaiwen W. Chen, Conos, Stephanie A, Chen, Kaiwen W, De Nardo, Dominic, Hara, Hideki, Whitehead, Lachlan, Nunez, Gabriel, Masters, Seth L, Murphy, James M, Schroder, Kate, Vaux, David L, Lawlor, Kate E, Lindqvist, Lisa M, and Vince, James E
- Subjects
0301 basic medicine ,Programmed cell death ,Multidisciplinary ,integumentary system ,interleukin-1β ,Necroptosis ,Pyroptosis ,Caspase 1 ,necroptosis ,Signal transducing adaptor protein ,Inflammasome ,Biology ,Gasdermin D ,Proinflammatory cytokine ,Cell biology ,Multidisciplinary Sciences ,03 medical and health sciences ,030104 developmental biology ,NLRP3 ,medicine ,Secretion ,MLKL ,medicine.drug - Abstract
Necroptosis is a physiological cell suicide mechanism initiated by receptor-interacting protein kinase-3 (RIPK3) phosphorylation of mixed-lineage kinase domain-like protein (MLKL), which results in disruption of the plasma membrane. Necroptotic cell lysis, and resultant release of proinflammatory mediators, is thought to cause inflammation in necroptotic disease models. However, we previously showed that MLKL signaling can also promote inflammation by activating the nucleotide-binding oligomerization domain (NOD)- like receptor protein 3 (NLRP3) inflammasome to recruit the adaptor protein apoptosis-Associated speck-like protein containing a caspase activation and recruitment domain (ASC) and trigger caspase-1 processing of the proinflammatory cytokine IL-1β. diseases. Here, we provide evidence that MLKL-induced activation of NLRP3 requires (i) the death effector four-helical bundle of MLKL, (ii) oligomerization and association of MLKL with cellular membranes, and (iii) a reduction in intracellular potassium concentration. Although genetic or pharmacological targeting of NLRP3 or caspase-1 prevented MLKLinduced IL-1β secretion, they did not prevent necroptotic cell death. Gasdermin D (GSDMD), the pore-forming caspase-1 substrate required for efficient NLRP3-Triggered pyroptosis and IL-1β release, was not essential for MLKL-dependent death or IL-1β secretion. Imaging of MLKL-dependent ASC speck formation demonstrated that necroptotic stimuli activate NLRP3 cell-intrinsically, indicating that MLKL-induced NLRP3 inflammasome formation and IL-1β cleavage occur before cell lysis. Furthermore, we show that necroptotic activation of NLRP3, but not necroptotic cell death alone, is necessary for the activation of NF-κB in healthy bystander cells. Collectively, these results demonstrate the potential importance of NLRP3 inflammasome activity as a driving force for inflammation in MLKLdependent Refereed/Peer-reviewed
- Published
- 2017
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