Dominant Negative Effects of Tumor Necrosis Factor (TNF)-related Apoptosis-inducing Ligand (TRAIL) Receptor 4 on TRAIL Receptor 1 Signaling by Formation of Heteromeric Complexes

Neumann, Simon; Hasenauer, Jan; Pollak, Nadine; Scheurich, Peter

doi:10.1074/jbc.m114.559468

Cited by 43 publications

(41 citation statements)

References 38 publications

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“…In agreement with the regulation by O ‐ or N ‐glycosylated death receptors, the upregulation of fucosylation changes the distribution of death receptors and enhances their clustering leading to enhanced apoptotic signal transduction after the stimulation by TRAIL . There is some evidence showing that a preligand assembly domain association (PLAD) consisting of death receptors, especially DR5, and decoy receptors lacking a death domain attenuates TRAIL‐induced apoptosis . In concert with this PLAD model, it can be conceived that if most death receptors are involved in the preclustering activity due to the upregulation of fucosylation, the possibility for them to bind to the decoy receptors greatly decreases.…”

Section: Discussionmentioning

confidence: 82%

Death receptor 5 is activated by fucosylation in colon cancer cells

et al. 2019

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The remarkable pro‐apoptotic properties of tumour necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL) have led to considerable interest in this protein as a potential anticancer therapeutic. However, TRAIL is largely ineffective in inducing apoptosis in certain cancer cells, and the mechanisms underlying this selectivity are unknown. In colon adenocarcinomas, posttranslational modifications including O‐ and N‐ glycosylation of death receptors were found to correlate with TRAIL‐induced apoptosis. Additionally, mRNA levels of fucosyltransferase 3 (FUT3) and 6 (FUT6) were found to be high in the TRAIL‐sensitive colon adenocarcinoma cell line COLO 205. In this study, we use agonistic receptor‐specific TRAIL variants to dissect the contribution of FUT3 and FUT6‐mediated fucosylation to TRAIL‐induced apoptosis via its two death receptors, DR4 and DR5. Triggering of apoptosis by TRAIL revealed that the low FUT3/6‐expressing cells DLD‐1 and HCT 116 are insensitive to DR5 but not to DR4‐mediated apoptosis. By contrast, efficient apoptosis is mediated via both receptors in high FUT3/6‐expressing COLO 205 cells. The reconstitution of FUT3/6 expression in DR5‐resistant cells completely restored TRAIL sensitivity via this receptor, while only marginally enhancing apoptosis via DR4 at lower TRAIL concentrations. Interestingly, we observed that induction of the salvage pathway by external administration of l‐fucose restores DR5‐mediated apoptosis in both DLD‐1 and HCT 116 cells. Finally, we show that fucosylation influences the ligand‐independent receptor association that leads to increased death inducing signalling complex (DISC) formation and caspase‐8 activation. Taken together, these results provide evidence for the differential impact of fucosylation on signalling via DR4 or DR5. These findings provide novel opportunities to enhance TRAIL sensitivity in colon adenocarcinoma cells that are highly resistant to DR5‐mediated apoptosis.

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Section: Discussionmentioning

confidence: 82%

Death receptor 5 is activated by fucosylation in colon cancer cells

et al. 2019

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“…Liver injury can cause hepatocyte necrosis and apoptosis, depending on the severity of the liver injury (Neumann et al, 2014). Hence, early hepatocyte damage could be detected by measuring K18 and ccK18 levels (Galluzzi et al, 2012).…”

Section: Major Biomarkersmentioning

confidence: 99%

Molecular Biomarkers in Drug-Induced Liver Injury: Challenges and Future Perspectives

Jiang

et al. 2020

Front. Pharmacol.

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Drug-induced liver injury (DILI) is one among the common adverse drug reactions and the leading causes of drug development attritions, black box warnings, and post-marketing withdrawals. Despite having relatively low clinical incidence, its potentially severe adverse events should be considered in the individual patients due to the high risk of acute liver failure. Although traditional liver parameters have been applied to the diagnosis of DILI, the lack of specific and sensitive biomarkers poses a major limitation, and thus accurate prediction of the subsequent clinical course remains a significant challenge. These drawbacks prompt the investigation and discovery of more effective biomarkers, which could lead to early detection of DILI, and improve its diagnosis and prognosis. Novel promising biomarkers include glutamate dehydrogenase, keratin 18, sorbitol dehydrogenase, glutathione S-transferase, bile acids, cytochrome P450, osteopontin, high mobility group box-1 protein, fatty acid binding protein 1, cadherin 5, miR-122, genetic testing, and omics technologies, among others. Furthermore, several clinical scoring systems have gradually emerged for the diagnosis of DILI including the Roussel Uclaf Causality Assessment Method (RUCAM), Clinical Diagnostic Scale (CDS), and Digestive Disease Week Japan (DDW-J) systems. However, currently their predictive value is limited with certain inherent deficiencies. Thus, perhaps the greatest benefit would be achieved by simultaneously combining the scoring systems and those biomarkers. Herein, we summarized the recent research progress on molecular biomarkers for DILI to improved approaches for its diagnosis and clinical management.

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“…It has been shown that the complex formation between death receptors TRAIL-R1 and TRAIL-R2 and the apoptosis-incompetent receptors, TRAIL-R3 or TRAIL-R4, leads to impaired DISC function. 33 , 34 In addition, recruitment of the proteolytically inactive caspase homolog cFLIP (cellular FLICE-like inhibitory protein) represents an apoptosis-inhibiting mechanism. 35 , 36 …”

Section: Trail Receptors and Their Classical Functions At The Plasma mentioning

confidence: 99%

Compartmentalization of TNF-related apoptosis-inducing ligand (TRAIL) death receptor functions: emerging role of nuclear TRAIL-R2

Bertsch¹,

Röder²,

Kalthoff³

et al. 2014

Cell Death Dis

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Localized in the plasma membrane, death domain-containing TNF-related apoptosis-inducing ligand (TRAIL) receptors, TRAIL-R1 and TRAIL-R2, induce apoptosis and non-apoptotic signaling when crosslinked by the ligand TRAIL or by agonistic receptor-specific antibodies. Recently, an increasing body of evidence has accumulated that TRAIL receptors are additionally found in noncanonical intracellular locations in a wide range of cell types, preferentially cancer cells. Thus, besides their canonical locations in the plasma membrane and in intracellular membranes of the secretory pathway as well as endosomes and lysosomes, TRAIL receptors may also exist in autophagosomes, in nonmembraneous cytosolic compartment as well as in the nucleus. Such intracellular locations have been mainly regarded as hide-outs for these receptors representing a strategy for cancer cells to resist TRAIL-mediated apoptosis. Recently, a novel function of intracellular TRAIL-R2 has been revealed. When present in the nuclei of tumor cells, TRAIL-R2 inhibits the processing of the primary let-7 miRNA (pri-let-7) via interaction with accessory proteins of the Microprocessor complex. The nuclear TRAIL-R2-driven decrease in mature let-7 enhances the malignancy of cancer cells. This finding represents a new example of nuclear activity of typically plasma membrane-located cytokine and growth factor receptors. Furthermore, this extends the list of nucleic acid targets of the cell surface receptors by pri-miRNA in addition to DNA and mRNA. Here we review the diverse functions of TRAIL-R2 depending on its intracellular localization and we particularly discuss the nuclear TRAIL-R2 (nTRAIL-R2) function in the context of known nuclear activities of other normally plasma membrane-localized receptors.

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Dominant Negative Effects of Tumor Necrosis Factor (TNF)-related Apoptosis-inducing Ligand (TRAIL) Receptor 4 on TRAIL Receptor 1 Signaling by Formation of Heteromeric Complexes

Cited by 43 publications

References 38 publications

Death receptor 5 is activated by fucosylation in colon cancer cells

Death receptor 5 is activated by fucosylation in colon cancer cells

Molecular Biomarkers in Drug-Induced Liver Injury: Challenges and Future Perspectives

Compartmentalization of TNF-related apoptosis-inducing ligand (TRAIL) death receptor functions: emerging role of nuclear TRAIL-R2

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