scholarly journals Roles for ADAM17 in TNF-R1 Mediated Cell Death and Survival in Human U937 and Jurkat Cells

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3100
Author(s):  
Jürgen Fritsch ◽  
Julia Frankenheim ◽  
Lothar Marischen ◽  
Timea Vadasz ◽  
Anja Troeger ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Fate ◽  
Inflammatory Diseases ◽  
Death Receptor ◽  
Cell Types ◽  
Jurkat Cells ◽  
Receptor Signaling ◽  
Genetic Ablation ◽  
Cell Fate Decisions ◽  
Death Receptor Signaling

Signaling via death receptor family members such as TNF-R1 mediates pleiotropic biological outcomes ranging from inflammation and proliferation to cell death. Pro-survival signaling is mediated via TNF-R1 complex I at the cellular plasma membrane. Cell death induction requires complex IIa/b or necrosome formation, which occurs in the cytoplasm. In many cell types, full apoptotic or necroptotic cell death induction requires the internalization of TNF-R1 and receptosome formation to properly relay the signal inside the cell. We interrogated the role of the enzyme A disintegrin and metalloprotease 17 (ADAM17)/TACE (TNF-α converting enzyme) in death receptor signaling in human hematopoietic cells, using pharmacological inhibition and genetic ablation. We show that in U937 and Jurkat cells the absence of ADAM17 does not abrogate, but rather increases TNF mediated cell death. Likewise, cell death triggered via DR3 is enhanced in U937 cells lacking ADAM17. We identified ADAM17 as the key molecule that fine-tunes death receptor signaling. A better understanding of cell fate decisions made via the receptors of the TNF-R1 superfamily may enable us, in the future, to more efficiently treat infectious and inflammatory diseases or cancer.

Beyond apoptosis: nonapoptotic cell death in physiology and disease

2005 ◽  
Vol 83 (5) ◽  
pp. 579-588 ◽  
Author(s):  
Claudio A Hetz ◽  
Vicente Torres ◽  
Andrew F.G Quest
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Death Receptor ◽  
Receptor Signaling ◽  
Family Analysis ◽  
Caspase Family ◽  
Death Receptor Signaling ◽  
Apoptotic Pathways ◽  
Nonapoptotic Cell Death ◽  
High Degree

Apoptosis is a morphologically defined form of programmed cell death (PCD) that is mediated by the activation of members of the caspase family. Analysis of death-receptor signaling in lymphocytes has revealed that caspase-dependent signaling pathways are also linked to cell death by nonapoptotic mechanisms, indicating that apoptosis is not the only form of PCD. Under physiological and pathological conditions, cells demonstrate a high degree of flexibility in cell-death responses, as is reflected in the existence of a variety of mechanisms, including necrosis-like PCD, autophagy (or type II PCD), and accidental necrosis. In this review, we discuss recent data suggesting that canonical apoptotic pathways, including death-receptor signaling, control caspase-dependent and -independent cell-death pathways.Key words: apoptosis, necrosis, nonapoptotic programmed cell death, death receptors, ceramides.

scholarly journals The Tumor Suppressor RASSF1A and MAP-1 Link Death Receptor Signaling to Bax Conformational Change and Cell Death

2005 ◽  
Vol 18 (6) ◽  
pp. 637-650 ◽  
Author(s):  
Shairaz Baksh ◽  
Stella Tommasi ◽  
Sarah Fenton ◽  
Victor C. Yu ◽  
L. Miguel Martins ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Suppressor ◽  
Conformational Change ◽  
Death Receptor ◽  
Receptor Signaling ◽  
Death Receptor Signaling

scholarly journals Hedgehog Inhibition Promotes a Switch from Type II to Type I Cell Death Receptor Signaling in Cancer Cells

PLoS ONE ◽  
2011 ◽  
Vol 6 (3) ◽  
pp. e18330 ◽  
Author(s):  
Satoshi Kurita ◽  
Justin L. Mott ◽  
Sophie C. Cazanave ◽  
Christian D. Fingas ◽  
Maria E. Guicciardi ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Death Receptor ◽  
Type I ◽  
Type Ii ◽  
Receptor Signaling ◽  
Death Receptor Signaling ◽  
Cell Death Receptor

scholarly journals Intracellular Hedgehog signaling controls Th17 polarization and pathogenicity

2021 ◽  
Author(s):  
Maike de la Roche ◽  
Joachim Hanna ◽  
Louise O'Brien ◽  
Chrysa Kapeni ◽  
Hung-Chang Chen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Cell Subset ◽  
T Helper 17 ◽  
Genetic Ablation ◽  
Cell Fate Decisions ◽  
Th17 Differentiation ◽  
Hh Signaling

Abstract T helper 17 (Th17) cells play a key role in barrier protection against fungal and bacterial pathogens but are also pathological drivers of many inflammatory diseases. Although the transcription factor networks governing Th17 differentiation are well defined, the signaling pathways that regulate the development and function of this important CD4+ T cell subset are still poorly understood. Hedgehog (Hh) signaling plays important roles in regulating cell fate decisions during embryogenesis and adult tissue patterning. Using novel CD4-specific Hh knockout mice, we find that intracellular Hh signaling, independently of exogenous Hh ligands, selectively drives Th17 lineage differentiation but not the development of Th1, Th2, or iTreg CD4+ Th cells. We show that the endogenous Indian Hh (Ihh) ligand signals via the signal transducer Smoothened to activate both canonical and non-canonical Hh pathways, through the Gli3 transcription factor and AMPK phosphorylation, respectively. Using two models of intestinal inflammation, we demonstrate that inhibition of the Hh pathway with either the clinically approved small molecule inhibitor vismodegib or genetic ablation of Ihh in CD4+ T cells greatly diminishes disease severity. Taken together, we have uncovered Hh as a novel signaling pathway controlling Th17 differentiation and Gli3 as a crucial transcription factor in this process. Our work paves the way for a potential use of Hh inhibitors in the treatment of inflammatory bowel disease and other autoimmune diseases.

scholarly journals Arginine-GlcNAcylation of death domain and NleB/SseK proteins is crucial for bacteria pathogenesis by regulating host cell death

2019 ◽  
Author(s):  
Juan Xue ◽  
Xing Pan ◽  
Lijie Du ◽  
Xiaohui Zhuang ◽  
Xiaobin Cai ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Necrosis Factor Receptor ◽  
Death Receptor ◽  
Receptor Signaling ◽  
Death Domain ◽  
Type Iii ◽  
Serovar Typhimurium ◽  
Death Receptor Signaling ◽  
Domain Protein

AbstractDeath receptor signaling is critical for cell death, inflammation, and immune homeostasis. Hijacking death receptors and their corresponding adaptors through type III secretion system (T3SS) effectors has been evolved to be a bacterial evasion strategy. NleB from enteropathogenic Escherichia coli (EPEC) and SseK1/2/3 from Salmonella enterica serovar Typhimurium (S. Typhimurium) can modify some death domains involved in death receptor signaling through arginine-GlcNAcylation. This study applied a limited substrate screen from 12 death domain proteins with conserved arginines during EPEC and Salmonella infection and found that NleB from EPEC hijacked death receptor signaling tumor necrosis factor receptor 1 (TNFR1)-associated death domain protein (TRADD), FAS-associated death domain protein (FADD), and receptor-interacting serine/threonine-protein kinase 1 (RIPK1), whereas SseK1 and SseK3 disturbed TNFR signaling through the modification of TRADD Arg235/245 and TNFR1 Arg376, respectively. SseK1 and SseK3 delivered by Salmonella inhibited TNF-α- but not TNF-related apoptosis-inducing ligand (TRAIL)-induced cell death, which was consistent with their host substrate recognition specificity. Taking advantage of the substrate specificity of SseK effectors, we found that only SseK1 fully rescued the bacteria colonization deficiency contributed by NleBc in Citrobacter rodentium infection animal model, indicating that TRADD was likely to be the preferred in vivo substrate corresponding to NleB/SseK1-induced bacterial virulence. Furthermore, novel auto-arginine-GlcNAcylation was observed in NleB and SseK1/3, which promoted the enzyme activity. These findings suggest that arginine-GlcNAcylation in death domains and auto-arginine-GlcNAcylation catalyzed by type III-translocated bacterial effector proteins NleB/SseKs are crucial for bacteria pathogenesis in regulating nuclear factor-κB (NF-κB) and death receptor signaling pathways. This study provides an insight into the mechanism by which EPEC and Salmonella manipulate death receptor signaling and evade host immune defense through T3SS effectors.Author SummaryEnteropathogenic Escherichia coli (EPEC) and Salmonella enterica serovar Typhimurium (S. Typhimurium) are important food-borne pathogens infecting the intestine. They deliver type III secretion system effector NleB/SseKs to modify host death domain proteins by arginine GlcNAcylation. We screened the modification of 12 death domains containing conserved arginine in human genome by NleB, SseK1, SseK2, and SseK3 through ectopic co-expression and bacterial infection. Unlike multiple death receptor signaling inhibition by NleB, we found that SseK1 and SseK3 specifically hijacked tumor necrosis factor receptor 1 (TNFR1)-mediated death signaling through targeting TNFR1-associated death domain protein (TRADD) and receptor TNFR1, respectively. We identified the modification sites and suggested that TRADD was the in vivo target of NleB in mice infection model by utilizing the substrate specificity of SseK1 and SseK3, which highlighted anti-bacterial infection role of TRADD in death receptor signaling and non-death receptor signaling. In addition to the modification on host death domain substrates, we firstly elucidated the effect of auto-modification of the arginine GlcNAc transferases on the enzymatic activity, which widened our understanding of the newly discovered post translational modification in the process of pathogen-host interaction.

scholarly journals The Roles of Chromatin Accessibility in Regulating the Candida albicans White-Opaque Phenotypic Switch

2021 ◽  
Vol 7 (1) ◽  
pp. 37
Author(s):  
Mohammad N. Qasim ◽  
Ashley Valle Arevalo ◽  
Clarissa J. Nobile ◽  
Aaron D. Hernday
Keyword(s):  
Candida Albicans ◽  
Cell Fate ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Phenotypic Switching ◽  
Phenotypic Switch ◽  
Chromatin Remodelers ◽  
Environmental Signals ◽  
Cell Fate Decisions ◽  
Simple Model System

Candida albicans, a diploid polymorphic fungus, has evolved a unique heritable epigenetic program that enables reversible phenotypic switching between two cell types, referred to as “white” and “opaque”. These cell types are established and maintained by distinct transcriptional programs that lead to differences in metabolic preferences, mating competencies, cellular morphologies, responses to environmental signals, interactions with the host innate immune system, and expression of approximately 20% of genes in the genome. Transcription factors (defined as sequence specific DNA-binding proteins) that regulate the establishment and heritable maintenance of the white and opaque cell types have been a primary focus of investigation in the field; however, other factors that impact chromatin accessibility, such as histone modifying enzymes, chromatin remodelers, and histone chaperone complexes, also modulate the dynamics of the white-opaque switch and have been much less studied to date. Overall, the white-opaque switch represents an attractive and relatively “simple” model system for understanding the logic and regulatory mechanisms by which heritable cell fate decisions are determined in higher eukaryotes. Here we review recent discoveries on the roles of chromatin accessibility in regulating the C. albicans white-opaque phenotypic switch.

scholarly journals Fatty Acids Metabolism: The Bridge Between Ferroptosis and Ionizing Radiation

2021 ◽  
Vol 9 ◽  
Author(s):  
Zhu-hui Yuan ◽  
Tong Liu ◽  
Hao Wang ◽  
Li-xiang Xue ◽  
Jun-jie Wang
Keyword(s):  
Fatty Acids ◽  
Cell Death ◽  
Ionizing Radiation ◽  
Cell Fate ◽  
Tumor Response ◽  
Cell Fate Decisions ◽  
Current Review ◽  
Pathway Crosstalk ◽  
Fatty Acids Metabolism ◽  
Molecular Signals

Exposure of tumor cells to ionizing radiation (IR) alters the microenvironment, particularly the fatty acid (FA) profile and activity. Moreover, abnormal FA metabolism, either catabolism or anabolism, is essential for synthesizing biological membranes and delivering molecular signals to induce ferroptotic cell death. The current review focuses on the bistable regulation characteristics of FA metabolism and explains how FA catabolism and anabolism pathway crosstalk harmonize different ionizing radiation-regulated ferroptosis responses, resulting in pivotal cell fate decisions. In summary, targeting key molecules involved in lipid metabolism and ferroptosis may amplify the tumor response to IR.

Serrate and Notch specify cell fates in the heart field by suppressing cardiomyogenesis

Development ◽  
2000 ◽  
Vol 127 (17) ◽  
pp. 3865-3876
Author(s):  
M.S. Rones ◽  
K.A. McLaughlin ◽  
M. Raffin ◽  
M. Mercola
Keyword(s):  
Gene Expression ◽  
Notch Signaling ◽  
Cell Fate ◽  
Notch Pathway ◽  
Cell Types ◽  
Myocardial Cell ◽  
Dominant Negative ◽  
Cell Fates ◽  
Cell Fate Decisions ◽  
Heart Field

Notch signaling mediates numerous developmental cell fate decisions in organisms ranging from flies to humans, resulting in the generation of multiple cell types from equipotential precursors. In this paper, we present evidence that activation of Notch by its ligand Serrate apportions myogenic and non-myogenic cell fates within the early Xenopus heart field. The crescent-shaped field of heart mesoderm is specified initially as cardiomyogenic. While the ventral region of the field forms the myocardial tube, the dorsolateral portions lose myogenic potency and form the dorsal mesocardium and pericardial roof (Raffin, M., Leong, L. M., Rones, M. S., Sparrow, D., Mohun, T. and Mercola, M. (2000) Dev. Biol., 218, 326–340). The local interactions that establish or maintain the distinct myocardial and non-myocardial domains have never been described. Here we show that Xenopus Notch1 (Xotch) and Serrate1 are expressed in overlapping patterns in the early heart field. Conditional activation or inhibition of the Notch pathway with inducible dominant negative or active forms of the RBP-J/Suppressor of Hairless [Su(H)] transcription factor indicated that activation of Notch feeds back on Serrate1 gene expression to localize transcripts more dorsolaterally than those of Notch1, with overlap in the region of the developing mesocardium. Moreover, Notch pathway activation decreased myocardial gene expression and increased expression of a marker of the mesocardium and pericardial roof, whereas inhibition of Notch signaling had the opposite effect. Activation or inhibition of Notch also regulated contribution of individual cells to the myocardium. Importantly, expression of Nkx2. 5 and Gata4 remained largely unaffected, indicating that Notch signaling functions downstream of heart field specification. We conclude that Notch signaling through Su(H) suppresses cardiomyogenesis and that this activity is essential for the correct specification of myocardial and non-myocardial cell fates.

Sign in / Sign up

Export Citation Format

Share Document