Death receptors

2003 ◽  
Vol 39 ◽  
pp. 53-71 ◽  
Author(s):  
Harald Wajant
Keyword(s):  
Molecular Mechanisms ◽  
Ectodermal Dysplasia ◽  
Death Receptor ◽  
Growth Factor Receptor ◽  
Death Receptors ◽  
Tnf Receptor ◽  
Death Domain ◽  
Receptor Signalling ◽  
Death Receptor 3 ◽  
Necrosis Factor

Death receptors [Fas/Apo-1/CD95, TNF-R1 [tumour necrosis factor (TNF) receptor 1], DR3 [death receptor 3], TRAIL-R1 [TNF-related apoptosis-inducing ligand receptor 1], TRAIL-R2, DR6, p75-NGFR [p75-nerve growth factor receptor], EDAR [ectodermal dysplasia receptor]] form a subgroup of the TNF-R superfamily that can induce apoptosis (programmed cell death) via a conserved cytoplasmic signalling module termed the death domain. Although death receptors have been recognized mainly as apoptosis inducers, there is growing evidence that these receptors also fulfil a variety of nonapoptotic functions. This review is focused on the molecular mechanisms of apoptotic and non-apoptotic death receptor signalling in light of the phenotype of mice deficient in the various death receptors.

scholarly journals Sweet modification and regulation of death receptor signalling pathway

2021 ◽  
Author(s):  
Kenta Moriwaki ◽  
Francis K M Chan ◽  
Eiji Miyoshi
Keyword(s):  
Critical Role ◽  
Immune Surveillance ◽  
Death Receptor ◽  
Death Receptors ◽  
Receptor Activation ◽  
Intracellular Signalling ◽  
Human Diseases ◽  
Tumour Necrosis Factor Receptor ◽  
Death Domain ◽  
Receptor Signalling

Abstract Death receptors, members of the tumour necrosis factor receptor (TNFR) superfamily, are characterized by the presence of a death domain in the cytosolic region. TNFR1, Fas and TNF-related apoptosis-inducing ligand receptors, which are prototypical death receptors, exert pleiotropic functions in cell death, inflammation and immune surveillance. Hence, they are involved in several human diseases. The activation of death receptors and downstream intracellular signalling is regulated by various posttranslational modifications, such as phosphorylation, ubiquitination and glycosylation. Glycosylation is one of the most abundant and versatile modifications to proteins and lipids, and it plays a critical role in the development and physiology of organisms, as well as the pathology of many human diseases. Glycans control a number of cellular events, such as receptor activation, signal transduction, endocytosis, cell recognition and cell adhesion. It has been demonstrated that oligo- and monosaccharides modify death receptors and intracellular signalling proteins and regulate their functions. Here, we review the current understanding of glycan modifications of death receptor signalling and their impact on signalling activity.

scholarly journals Inhibition of TRAIL-Induced Apoptosis and Forced Internalization of TRAIL Receptor 1 by Adenovirus Proteins

2001 ◽  
Vol 75 (19) ◽  
pp. 8875-8887 ◽  
Author(s):  
Ann E. Tollefson ◽  
Karoly Toth ◽  
Konstantin Doronin ◽  
Mohan Kuppuswamy ◽  
Oksana A. Doronina ◽  
...  
Keyword(s):  
Fas Ligand ◽  
Death Receptor ◽  
Growth Factor Receptor ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Death Receptor 5 ◽  
Tnf Receptor ◽  
Death Domain ◽  
Virus Infections ◽  
Induced Apoptosis

ABSTRACT Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis through two receptors, TRAIL-R1 (also known as death receptor 4) and TRAIL-R2 (also known as death receptor 5), that are members of the TNF receptor superfamily of death domain-containing receptors. We show that human adenovirus type 5 encodes three proteins, named RID (previously named E3-10.4K/14.5K), E3-14.7K, and E1B-19K, that independently inhibit TRAIL-induced apoptosis of infected human cells. This conclusion was derived from studies using wild-type adenovirus, adenovirus replication-competent mutants that lack one or more of the RID,E3-14.7K, and E1B-19K genes, and adenovirus E1-minus replication-defective vectors that express all E3 genes, RID plus E3-14.7K only, RID only, or E3-14.7K only. RID inhibits TRAIL-induced apoptosis when cells are sensitized to TRAIL either by adenovirus infection or treatment with cycloheximide. RID induces the internalization of TRAIL-R1 from the cell surface, as shown by flow cytometry and indirect immunofluorescence for TRAIL-R1. TRAIL-R1 was internalized in distinct vesicles which are very likely to be endosomes and lysosomes. TRAIL-R1 is degraded, as indicated by the disappearance of the TRAIL-R1 immunofluorescence signal. Degradation was inhibited by bafilomycin A1, a drug that prevents acidification of vesicles and the sorting of receptors from late endosomes to lysosomes, implying that degradation occurs in lysosomes. RID was also shown previously to internalize and degrade another death domain receptor, Fas, and to prevent apoptosis through Fas and the TNF receptor. RID was shown previously to force the internalization and degradation of the epidermal growth factor receptor. E1B-19K was shown previously to block apoptosis through Fas, and both E1B-19K and E3-14.7K were found to prevent apoptosis through the TNF receptor. These findings suggest that the receptors for TRAIL, Fas ligand, and TNF play a role in limiting virus infections. The ability of adenovirus to inhibit killing through these receptors may prolong acute and persistent infections.

scholarly journals The C-terminal Tails of Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) and Fas Receptors Have Opposing Functions in Fas-associated Death Domain (FADD) Recruitment and Can Regulate Agonist-specific Mechanisms of Receptor Activation

2004 ◽  
Vol 279 (50) ◽  
pp. 52479-52486 ◽  
Author(s):  
Lance R. Thomas ◽  
Ronald L. Johnson ◽  
John C. Reed ◽  
Andrew Thorburn
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Molecular Mechanisms ◽  
Death Receptor ◽  
Receptor Activation ◽  
Death Domain ◽  
Absolute Requirement ◽  
Trail Receptors ◽  
Domain Interactions ◽  
Necrosis Factor

Members of the tumor necrosis factor (TNF) superfamily of receptors such as Fas/CD95 and the TNF-related apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5 induce apoptosis by recruiting adaptor molecules and caspases. The central adaptor molecule for these receptors is a death domain-containing protein, FADD, which binds to the activated receptor via death domain-death domain interactions. Here, we show that in addition to the death domain, the C-terminal tails of DR4 and DR5 positively regulate FADD binding, caspase activation and apoptosis. In contrast, the corresponding region in the Fas receptor has the opposite effect and inhibits binding to the receptor death domain. Replacement of wild-type or mutant DR5 molecules into DR5-deficient BJAB cells indicates that some agonistic antibodies display an absolute requirement for the C-terminal tail for FADD binding and signaling while other antibodies can function in the absence of this mechanism. These data demonstrate that regions outside the death domains of DR4 and DR5 have opposite effects to that of Fas in regulating FADD recruitment and show that different death receptor agonists can use distinct molecular mechanisms to activate signaling from the same receptor.

scholarly journals Reovirus-Induced Apoptosis Is Mediated by TRAIL

2000 ◽  
Vol 74 (17) ◽  
pp. 8135-8139 ◽  
Author(s):  
Penny Clarke ◽  
Suzanne M. Meintzer ◽  
Spencer Gibson ◽  
Christian Widmann ◽  
Timothy P. Garrington ◽  
...  
Keyword(s):  
Death Receptor ◽  
Tnf Receptor ◽  
Death Domain ◽  
Apoptotic Pathway ◽  
Cellular Receptors ◽  
Trail Receptors ◽  
Infected Cells ◽  
Soluble Trail ◽  
Induced Apoptosis ◽  
Necrosis Factor

ABSTRACT Members of the tumor necrosis factor (TNF) receptor superfamily and their activating ligands transmit apoptotic signals in a variety of systems. We now show that the binding of TNF-related, apoptosis-inducing ligand (TRAIL) to its cellular receptors DR5 (TRAILR2) and DR4 (TRAILR1) mediates reovirus-induced apoptosis. Anti-TRAIL antibody and soluble TRAIL receptors block reovirus-induced apoptosis by preventing TRAIL-receptor binding. In addition, reovirus induces both TRAIL release and an increase in the expression of DR5 and DR4 in infected cells. Reovirus-induced apoptosis is also blocked following inhibition of the death receptor-associated, apoptosis-inducing molecules FADD (for FAS-associated death domain) and caspase 8. We propose that reovirus infection promotes apoptosis via the expression of DR5 and the release of TRAIL from infected cells. Virus-induced regulation of the TRAIL apoptotic pathway defines a novel mechanism for virus-induced apoptosis.

scholarly journals The α and β Subunits of IκB Kinase (IKK) Mediate TRAF2-Dependent IKK Recruitment to Tumor Necrosis Factor (TNF) Receptor 1 in Response to TNF

2001 ◽  
Vol 21 (12) ◽  
pp. 3986-3994 ◽  
Author(s):  
Anne Devin ◽  
Yong Lin ◽  
Shoji Yamaoka ◽  
Zhiwei Li ◽  
Michael Karin ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Leucine Zipper ◽  
Nuclear Translocation ◽  
Ring Finger ◽  
Tnf Receptor ◽  
Death Domain ◽  
Iκb Kinase ◽  
Cytokine Tumor Necrosis Factor ◽  
Necrosis Factor

ABSTRACT The activation of IκB kinase (IKK) is a key step in the nuclear translocation of the transcription factor NF-κB. IKK is a complex composed of three subunits: IKKα, IKKβ, and IKKγ (also called NEMO). In response to the proinflammatory cytokine tumor necrosis factor (TNF), IKK is activated after being recruited to the TNF receptor 1 (TNF-R1) complex via TNF receptor-associated factor 2 (TRAF2). We found that the IKKα and IKKβ catalytic subunits are required for IKK-TRAF2 interaction. This interaction occurs through the leucine zipper motif common to IKKα, IKKβ, and the RING finger domain of TRAF2, and either IKKα or IKKβ alone is sufficient for the recruitment of IKK to TNF-R1. Importantly, IKKγ is not essential for TNF-induced IKK recruitment to TNF-R1, as this occurs efficiently in IKKγ-deficient cells. Using TRAF2−/− cells, we demonstrated that the TNF-induced interaction between IKKγ and the death domain kinase RIP is TRAF2 dependent and that one possible function of this interaction is to stabilize the IKK complex when it interacts with TRAF2.

scholarly journals Molecular Mode of Action of TRAIL Receptor Agonists—Common Principles and Their Translational Exploitation

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 954 ◽  
Author(s):  
Wajant
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Clinical Studies ◽  
Molecular Mechanisms ◽  
Death Receptor ◽  
Death Receptors ◽  
Maximum Activity ◽  
Receptor Agonists ◽  
Receptor Antibodies ◽  
Trail Death Receptor

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptors TRAILR1/death receptor 4 (DR4) and TRAILR2/DR5 trigger cell death in many cancer cells but rarely exert cytotoxic activity on non-transformed cells. Against this background, a variety of recombinant TRAIL variants and anti-TRAIL death receptor antibodies have been developed and tested in preclinical and clinical studies. Despite promising results from mice tumor models, TRAIL death receptor targeting has failed so far in clinical studies to show satisfying anti-tumor efficacy. These disappointing results can largely be explained by two issues: First, tumor cells can acquire TRAIL resistance by several mechanisms defining a need for combination therapies with appropriate sensitizing drugs. Second, there is now growing preclinical evidence that soluble TRAIL variants but also bivalent anti-TRAIL death receptor antibodies typically require oligomerization or plasma membrane anchoring to achieve maximum activity. This review discusses the need for oligomerization and plasma membrane attachment for the activity of TRAIL death receptor agonists in view of what is known about the molecular mechanisms of how TRAIL death receptors trigger intracellular cell death signaling. In particular, it will be highlighted which consequences this has for the development of next generation TRAIL death receptor agonists and their potential clinical application.

scholarly journals Tumor Necrosis Factor (TNF) Receptor Expression Determines Keratinocyte Fate upon Stimulation with TNF-Like Weak Inducer of Apoptosis

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Xuening Wang ◽  
Dan Cheng ◽  
Guanglei Hu ◽  
Lili Liang ◽  
Fei Tan ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Receptor Expression ◽  
Structural Basis ◽  
Tnf Receptor ◽  
Death Domain ◽  
Independent Manner ◽  
Normal Keratinocytes ◽  
Apoptosis Protein ◽  
Necrosis Factor

The interaction between tumor necrosis factor- (TNF-) like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible 14 (Fn14) regulates the fate of keratinocytes, depending on the relative expression of TNF receptor (TNFR) 1 or TNFR2. However, the precise mechanism underlying this TWEAK-mediated regulation remains unclear. The aim of this study was to provide comprehensive insight into the roles of Fn14, TNFR1/2, and other relevant molecules in the fate of keratinocytes. Further, we sought to elucidate the structural basis for the interaction of TWEAK and Fn14 in regulating cellular outcomes. Normal keratinocytes (mainly expressing TNFR1) and TNFR2-overexpressing keratinocytes were stimulated with TWEAK. Through immunoprecipitation and Western blotting of keratinocyte lysates, we elucidated the associations between Fn14, TNFR-associated factor 2 (TRAF2), cellular inhibitor of apoptosis protein 1 (cIAP1), and TNFR1/2 molecules. Additionally, we found that TRAF2 exhibited binding to Fn14, cIAP1, and TNFR1/2. Our data suggest that TWEAK induces apoptosis in normal keratinocytes and proliferation in TNFR2-overexpressing keratinocytes in a TNF-α-independent manner; however, inhibition of TRAF2 appears to reverse this effect. Interestingly, the interaction between TWEAK and Fn14 increased TNFR1-associated death domain protein and caspase-8 expression in normal keratinocytes and promoted cytoplasmic import of cIAP1 in TNFR2-overexpressing keratinocytes. In conclusion, we found that the Fn14-TRAF2-TNFR signaling axis mediates TWEAK’s regulation of the fate of keratinocytes, possibly in a manner involving the TNF-α-independent TNFR signal transduction.

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.

scholarly journals Dynamics of RASSF1A/MOAP-1 Association with Death Receptors

2008 ◽  
Vol 28 (14) ◽  
pp. 4520-4535 ◽  
Author(s):  
Caitlin J. Foley ◽  
Holly Freedman ◽  
Sheryl L. Choo ◽  
Christina Onyskiw ◽  
Nai Yang Fu ◽  
...  
Keyword(s):  
Tumor Necrosis Factor Receptor ◽  
Death Receptor ◽  
Death Receptors ◽  
Tumor Formation ◽  
Receptor Interaction ◽  
Binding Motif ◽  
Death Domain ◽  
Interacting Protein ◽  
Receptor Complexes ◽  
Tnf Α

ABSTRACT RASSF1A is a tumor suppressor protein involved in death receptor-dependent apoptosis utilizing the Bax-interacting protein MOAP-1 (previously referred to as MAP-1). However, the dynamics of death receptor recruitment of RASSF1A and MOAP-1 are still not understood. We have now detailed recruitment to death receptors (tumor necrosis factor receptor 1 [TNF-R1] and TRAIL-R1/DR4) and identified domains of RASSF1A and MOAP-1 that are required for death receptor interaction. Upon TNF-α stimulation, the C-terminal region of MOAP-1 associated with the death domain of TNF-R1; subsequently, RASSF1A was recruited to MOAP-1/TNF-R1 complexes. Prior to recruitment to TNF-R1/MOAP-1 complexes, RASSF1A homodimerization was lost. RASSF1A associated with the TNF-R1/MOAP-1 or TRAIL-R1/MOAP-1 complex via its N-terminal cysteine-rich (C1) domain containing a potential zinc finger binding motif. Importantly, TNF-R1 association domains on both MOAP-1 and RASSF1A were essential for death receptor-dependent apoptosis. The association of RASSF1A and MOAP-1 with death receptors involves an ordered recruitment to receptor complexes to promote cell death and inhibit tumor formation.

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