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Interactions of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (TRAIL) with the Immune System: Implications for Inflammation and Cancer
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TRAIL Induces Nuclear Translocation and Chromatin Localization of TRAIL Death Receptors

1
Institute for Experimental Cancer Research, University of Kiel, 24105 Kiel, Germany
2
Department of Clinical Chemistry, University Medical Centre, Ruprecht-Karls University of Heidelberg, 68167 Mannheim, Germany
3
Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany
4
Department of Translational Genomics, Medical Faculty, University of Cologne, 50931 Cologne, Germany
5
CECAD Research Center, Medical Faculty, University of Cologne, 50931 Cologne, Germany
6
Department of Infection Prevention and Infectious Diseases, University of Regensburg, 93053 Regensburg, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2019, 11(8), 1167; https://doi.org/10.3390/cancers11081167
Received: 2 August 2019 / Accepted: 8 August 2019 / Published: 14 August 2019
(This article belongs to the Special Issue TRAIL Signaling in Cancer Cells)
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Abstract

Binding of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to the plasma membrane TRAIL-R1/-R2 selectively kills tumor cells. This discovery led to evaluation of TRAIL-R1/-R2 as targets for anti-cancer therapy, yet the corresponding clinical trials were disappointing. Meanwhile, it emerged that many cancer cells are TRAIL-resistant and that TRAIL-R1/-R2-triggering may lead to tumor-promoting effects. Intriguingly, recent studies uncovered specific functions of long ignored intracellular TRAIL-R1/-R2, with tumor-promoting functions of nuclear (n)TRAIL-R2 as the regulator of let-7-maturation. As nuclear trafficking of TRAIL-Rs is not well understood, we addressed this issue in our present study. Cell surface biotinylation and tracking of biotinylated proteins in intracellular compartments revealed that nTRAIL-Rs originate from the plasma membrane. Nuclear TRAIL-Rs-trafficking is a fast process, requiring clathrin-dependent endocytosis and it is TRAIL-dependent. Immunoprecipitation and immunofluorescence approaches revealed an interaction of nTRAIL-R2 with the nucleo-cytoplasmic shuttle protein Exportin-1/CRM-1. Mutation of a putative nuclear export sequence (NES) in TRAIL-R2 or the inhibition of CRM-1 by Leptomycin-B resulted in the nuclear accumulation of TRAIL-R2. In addition, TRAIL-R1 and TRAIL-R2 constitutively localize to chromatin, which is strongly enhanced by TRAIL-treatment. Our data highlight the novel role for surface-activated TRAIL-Rs by direct trafficking and signaling into the nucleus, a previously unknown signaling principle for cell surface receptors that belong to the TNF-superfamily. View Full-Text
Keywords: TRAIL; nuclear TRAIL-R1; nuclear TRAIL-R2; trafficking; CRM-1 TRAIL; nuclear TRAIL-R1; nuclear TRAIL-R2; trafficking; CRM-1
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Mert, U.; Adawy, A.; Scharff, E.; Teichmann, P.; Willms, A.; Haselmann, V.; Colmorgen, C.; Lemke, J.; von Karstedt, S.; Fritsch, J.; Trauzold, A. TRAIL Induces Nuclear Translocation and Chromatin Localization of TRAIL Death Receptors. Cancers 2019, 11, 1167.

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