scholarly journals sFasL—The Key to a Riddle: Immune Responses in Aging Lung and Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 2177
Author(s):  
Shulamit B. Wallach-Dayan ◽  
Dmytro Petukhov ◽  
Ronit Ahdut-HaCohen ◽  
Mark Richter-Dayan ◽  
Raphael Breuer
Keyword(s):  
Cell Death ◽  
Lung Disease ◽  
Fas Ligand ◽  
Death Receptor ◽  
Mesenchymal Cells ◽  
Soluble Form ◽  
Cell Accumulation ◽  
Key Factor ◽  
Aged Subjects

By dint of the aging population and further deepened with the Covid-19 pandemic, lung disease has turned out to be a major cause of worldwide morbidity and mortality. The condition is exacerbated when the immune system further attacks the healthy, rather than the diseased, tissue within the lung. Governed by unremittingly proliferating mesenchymal cells and increased collagen deposition, if inflammation persists, as frequently occurs in aging lungs, the tissue develops tumors and/or turns into scars (fibrosis), with limited regenerative capacity and organ failure. Fas ligand (FasL, a ligand of the Fas cell death receptor) is a key factor in the regulation of these processes. FasL is primarily found in two forms: full length (membrane, or mFasL) and cleaved (soluble, or sFasL). We and others found that T-cells expressing the mFasL retain autoimmune surveillance that controls mesenchymal, as well as tumor cell accumulation following an inflammatory response. However, mesenchymal cells from fibrotic lungs, tumor cells, or cells from immune-privileged sites, resist FasL+ T-cell-induced cell death. The mechanisms involved are a counterattack of immune cells by FasL, by releasing a soluble form of FasL that competes with the membrane version, and inhibits their cell death, promoting cell survival. This review focuses on understanding the previously unrecognized role of FasL, and in particular its soluble form, sFasL, in the serum of aged subjects, and its association with the evolution of lung disease, paving the way to new methods of diagnosis and treatment.

Abstract 507: Activation of the Classically Pro-Apoptotic Death Receptor 5 Promotes Physiological Hypertrophy and Cardiomyocyte Survival

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Toby Thomas ◽  
Miles Tanner ◽  
Laurel Grisanti
Keyword(s):  
Heart Failure ◽  
Cell Death ◽  
Cardiac Fibrosis ◽  
Death Receptor ◽  
Protective Role ◽  
Cardiomyocyte Hypertrophy ◽  
Death Receptor 5 ◽  
Tnf Α ◽  
Cardiomyocyte Survival

Heart failure is hallmarked by a combination of cardiomyocyte hypertrophy and death. Apoptosis, one of the primary mechanisms of cell death, occurs through finely tuned extrinsic or intrinsic pathways. Of the mediators involved in extrinsic apoptotic signaling, some have been extensively studied, such as tumor necrosis factor ((TNF)-α), while others have been relatively untouched. One such receptor is Death Receptor 5 (DR5) which, along with its ligand TNF-Related Apoptosis Inducing Ligand (TRAIL), have recently been implicated as a biomarker in determining the progression and outcome in patients following multiple heart failure etiologies, suggesting a novel role of DR5 signaling in the heart. These studies suggest a potentially protective role for DR5 in the heart; however, the function of TRAIL/DR5 in the heart has been virtually unstudied. Our goal was to explore the role of TRAIL/DR5 in cardiomyocyte hypertrophy and survival with the hypothesis that DR5 promotes cardiomyocyte survival and growth through non-canonical mechanisms. Mice treated with the DR5 agonist bioymifi or a DR5 agonist antibody, MD5-1, were absent of cell death, while an increase in hypertrophy was observed without a decline in cardiac function. In isolated cardiomyocytes, this pro-hypertrophic phenotype was determined to operate through MMP-dependent cleavage of HB-EGFR, leading to transactivation of EGFR and ERK1/2 signaling. To determine the role of DR5 in heart failure, a chronic catecholamine administration model was used and DR5 activation was found to decrease cardiomyocyte death and cardiac fibrosis. ERK1/2, a well characterized pro-survival, pro-hypertrophic kinase is activated in the heart with DR5 agonist administration and may represent the mechanistic link through which DR5 is imparting cardioprotection. In summary, DR5 activation promotes cardiomyocyte hypertrophy and survival and prevents cardiac fibrosis via a non-canonical MMP-EGFR-ERK1/2 pathway. Taken together, these studies identify a previously undetermined role for DR5 in the heart and identify novel therapeutic target for the treatment of heart failure.

scholarly journals TVB Receptors for Cytopathic and Noncytopathic Subgroups of Avian Leukosis Viruses Are Functional Death Receptors

2000 ◽  
Vol 74 (24) ◽  
pp. 11490-11494 ◽  
Author(s):  
Jürgen Brojatsch ◽  
John Naughton ◽  
Heather B. Adkins ◽  
John A. T. Young
Keyword(s):  
Cell Death ◽  
Viral Infections ◽  
Tumor Necrosis Factor Receptor ◽  
Death Receptor ◽  
Death Receptors ◽  
Death Domain ◽  
Cytopathic Effects ◽  
Receptor Interactions ◽  
Surface Envelope

ABSTRACT The identification of TVBS3, a cellular receptor for the cytopathic subgroups B and D of avian leukosis virus (ALV-B and ALV-D), as a tumor necrosis factor receptor-related death receptor with a cytoplasmic death domain, provides a compelling argument that viral Env-receptor interactions are linked to cell death (4). However, other TVB proteins have been described that appear to have similar death domains but are cellular receptors for the noncytopathic subgroup E of ALV (ALV-E): TVBT, a turkey subgroup E-specific ALV receptor, and TVBS1, a chicken receptor for subgroups B, D, and E ALV. To begin to understand the role of TVB receptors in the cytopathic effects associated with infection by specific ALV subgroups, we asked whether binding of a soluble ALV-E surface envelope protein (SU) to its receptor can lead to cell death. Here we report that ALV-E SU-receptor interactions can induce apoptosis in quail or turkey cells. We also show directly that TVBS1and TVBT are functional death receptors that can trigger cell death by apoptosis via a mechanism involving their cytoplasmic death domains and activation of the caspase pathway. These data demonstrate that ALV-B and ALV-E use functional death receptors to enter cells, and it remains to be determined why only subgroups B and D viral infections lead specifically to cell death.

Arsenic Trioxide-Induced Cell Death Occurs Partially Independent of the Pro-Apoptotic Bcl-2-Family Members Bax and Bak.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4585-4585
Author(s):  
Christian Scholz ◽  
Antje Richter ◽  
Anja Richter ◽  
Bernd Dörken ◽  
Peter T. Daniel
Keyword(s):  
Cell Death ◽  
Arsenic Trioxide ◽  
Cell Lines ◽  
Apoptotic Cell ◽  
Family Members ◽  
Death Receptor ◽  
Hematologic Malignancies ◽  
Mitochondrial Pathway ◽  
Cell Death Pathways

Abstract Arsenic trioxide (As2O3, arsenite) efficiently kills cells from various hematologic malignancies and has successfully been employed for the treatment of acute promyelocytic leukaemia, myelodysplastic syndrome, and multiple myeloma. Investigating the mechanisms of arsenic trioxide-induced cell death, we recently demonstrated that arsenite-mediated cell demise has a partially necrotic phenotype, occurs independently of the extrinsic death receptor pathway of apoptosis, and is not hampered by the absence of functioning caspases. On the contrary, cell death proceeded entirely via an intrinsic, mitochondrial pathway and was efficiently blocked by the anti-apoptotic Bcl-2 family members Bcl-2 or Bcl-xL. Here, we address the role of the pro-apoptotic multi-domain Bcl-2 family members Bax and Bak. By employing different cell lines deficient for Bax and/or Bak, we demonstrate that Bax- or Bak-deficiency as well as the combined absence only partially blocks arsenite-induced cell death. While the detection of an additive effect of the combined Bax-/Bak-deficiency argues for a non redundant function of Bax and Bak, the persistence of a substantial percentage of arsenite-mediated cell demise in different double deficient cell lines nevertheless suggests a mode of arsenic trioxide-mediated cell death independent from these central inducers of apoptotic cell demise. The presented data add to the notion that arsenic trioxide kills tumor cells independent of the apoptotic machinery, and warrants further investigation on the efficacy of this compound in malignancies with deficiencies of the apoptotic cell death pathways.

Fluoroquinolone Eye Drop–Induced Cytotoxicity: Role of Preservative in P2X7 Cell Death Receptor Activation and Apoptosis

2006 ◽  
Vol 47 (7) ◽  
pp. 2812 ◽  
Author(s):  
Me´lody Dutot ◽  
Franc¸ois Pouzaud ◽  
Isabelle Larosche ◽  
Franc¸oise Brignole-Baudouin ◽  
Jean-Michel Warnet ◽  
...  
Keyword(s):  
Cell Death ◽  
Death Receptor ◽  
Receptor Activation ◽  
Cell Death Receptor

scholarly journals CD95/Fas ligand mRNA is toxic to cells

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Will Putzbach ◽  
Ashley Haluck-Kangas ◽  
Quan Q Gao ◽  
Aishe A Sarshad ◽  
Elizabeth T Bartom ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Fate ◽  
Fas Ligand ◽  
Death Receptor ◽  
Protein Translation ◽  
Similar Form ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
Endogenous Protein ◽  
Critical Survival

CD95/Fas ligand binds to the death receptor CD95 to induce apoptosis in sensitive cells. We previously reported that CD95L mRNA is enriched in sequences that, when converted to si/shRNAs, kill all cancer cells by targeting critical survival genes (<xref ref-type="bibr" rid="bib27">Putzbach et al., 2017</xref>). We now report expression of full-length CD95L mRNA itself is highly toxic to cells and induces a similar form of cell death. We demonstrate that small (s)RNAs derived from CD95L are loaded into the RNA induced silencing complex (RISC) which is required for the toxicity and processing of CD95L mRNA into sRNAs is independent of both Dicer and Drosha. We provide evidence that in addition to the CD95L transgene a number of endogenous protein coding genes involved in regulating protein translation, particularly under low miRNA conditions, can be processed to sRNAs and loaded into the RISC suggesting a new level of cell fate regulation involving RNAi.

scholarly journals Mitochondrial Regulation of Cell Death: Mitochondria Are Essential for Procaspase 3-p21 Complex Formation To Resist Fas-Mediated Cell Death

1999 ◽  
Vol 19 (5) ◽  
pp. 3842-3847 ◽  
Author(s):  
Atsushi Suzuki ◽  
Yumi Tsutomi ◽  
Naoe Yamamoto ◽  
Tomoko Shibutani ◽  
Kouichi Akahane
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Complex Formation ◽  
Fas Ligand ◽  
Actinomycin D ◽  
Death Receptor ◽  
Mitochondrial Fraction ◽  
Functional Region ◽  
Mitochondrial Regulation ◽  
Cell Death Signaling

ABSTRACT Death receptor Fas transduces cell death signaling upon stimulation by Fas ligand, and this death signaling is mediated by caspase. Recently, we reported that the cell cycle regulator p21 interacts with procaspase 3 to resist Fas-mediated cell death. In the present study, the molecular characterization and functional region of the procaspase 3-p21 complex was further investigated. We observed the p21 expression in the mitochondrial fraction of HepG2 cells and detected Fas-mediated cell death only in the presence of actinomycin D. However, mitochondrial-DNA-lacking HepG2 (MDLH) cells showed this effect even in the absence of actinomycin D. Both p21 and procaspase 3 were expressed in MDLH cells, but the procaspase 3-p21 complex formation was not observed. Interestingly, the resistance to Fas-mediated cell death in the MDLH cells without actinomycin D was recovered after microinjection of HepG2-derived mitochondria into the MDLH cells. We conclude that mitochondria are necessary for procaspase 3-p21 complex formation and propose that the mitochondrial role during cell death is not only death induction but also death suppression.

P2-209: Evaluation and modulation of toxic degenerative pathways induced by beta-amyloid on retinal cells: Role of P2X7 cell death receptor

2011 ◽  
Vol 7 ◽  
pp. S379-S380 ◽  
Author(s):  
Patrice Rat ◽  
Anais Wakx ◽  
Berengere De Moucheron ◽  
Melody Dutot ◽  
Olivier Laprevote
Keyword(s):  
Cell Death ◽  
Death Receptor ◽  
Beta Amyloid ◽  
Retinal Cells ◽  
Cell Death Receptor

scholarly journals CD95/Fas ligand mRNA is toxic to cells

2018 ◽  
Author(s):  
William Putzbach ◽  
Ashley Haluck-Kangas ◽  
Quan Q. Gao ◽  
Aishe A. Sarshad ◽  
Elizabeth T. Bartom ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Fate ◽  
Fas Ligand ◽  
Death Receptor ◽  
Protein Translation ◽  
Similar Form ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
Endogenous Protein ◽  
Critical Survival

AbstractCD95/Fas ligand binds to the death receptor CD95 to induce apoptosis in sensitive cells. We previously reported the CD95L mRNA is enriched in sequences that, when converted to si/shRNAs, kill all cancer cells by targeting critical survival genes (Putzbach et al., 2017). We now report expression of full-length CD95L mRNA, itself, is highly toxic to cells and induces a similar form of cell death. We demonstrate that small (s)RNAs derived from CD95L are loaded into the RNA induced silencing complex (RISC) RISC which is required for the toxicity and that processing of CD95L mRNA into sRNAs is independent of both Dicer and Drosha. We provide evidence that in addition to the CD95L transgene a number of endogenous protein coding genes involved in regulating protein translation, particularly under low miRNA conditions, can be processed to sRNAs and loaded into the RISC suggesting a new level of cell fate regulation involving RNAi.

scholarly journals Two Adjacent Trimeric Fas Ligands Are Required for Fas Signaling and Formation of a Death-Inducing Signaling Complex

2003 ◽  
Vol 23 (4) ◽  
pp. 1428-1440 ◽  
Author(s):  
Nils Holler ◽  
Aubry Tardivel ◽  
Magdalena Kovacsovics-Bankowski ◽  
Sylvie Hertig ◽  
Olivier Gaide ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Fas Ligand ◽  
Death Receptor ◽  
Receptor Activation ◽  
Soluble Form ◽  
Target Cells ◽  
Signaling Complex ◽  
Fas Signaling ◽  
Soluble Fasl ◽  
Membrane Bound

ABSTRACT The membrane-bound form of Fas ligand (FasL) signals apoptosis in target cells through engagement of the death receptor Fas, whereas the proteolytically processed, soluble form of FasL does not induce cell death. However, soluble FasL can be rendered active upon cross-linking. Since the minimal extent of oligomerization of FasL that exerts cytotoxicity is unknown, we engineered hexameric proteins containing two trimers of FasL within the same molecule. This was achieved by fusing FasL to the Fc portion of immunoglobulin G1 or to the collagen domain of ACRP30/adiponectin. Trimeric FasL and hexameric FasL both bound to Fas, but only the hexameric forms were highly cytotoxic and competent to signal apoptosis via formation of a death-inducing signaling complex. Three sequential early events in Fas-mediated apoptosis could be dissected, namely, receptor binding, receptor activation, and recruitment of intracellular signaling molecules, each of which occurred independently of the subsequent one. These results demonstrate that the limited oligomerization of FasL, and most likely of some other tumor necrosis factor family ligands such as CD40L, is required for triggering of the signaling pathways.

Sign in / Sign up

Export Citation Format

Share Document