TRAIL Induces Nuclear Translocation and Chromatin Localization of TRAIL Death Receptors
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 e...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/8/1167 |
| _version_ | 1797708327808925696 |
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| author | Ufuk Mert Alshaimaa Adawy Elisabeth Scharff Pierre Teichmann Anna Willms Verena Haselmann Cynthia Colmorgen Johannes Lemke Silvia von Karstedt Jürgen Fritsch Anna Trauzold |
| author_facet | Ufuk Mert Alshaimaa Adawy Elisabeth Scharff Pierre Teichmann Anna Willms Verena Haselmann Cynthia Colmorgen Johannes Lemke Silvia von Karstedt Jürgen Fritsch Anna Trauzold |
| author_sort | Ufuk Mert |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T06:20:52Z |
| format | Article |
| id | doaj.art-71db7d2a031d4f8e937bcca8d1d4f662 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T06:20:52Z |
| publishDate | 2019-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-71db7d2a031d4f8e937bcca8d1d4f6622023-09-03T02:15:41ZengMDPI AGCancers2072-66942019-08-01118116710.3390/cancers11081167cancers11081167TRAIL Induces Nuclear Translocation and Chromatin Localization of TRAIL Death ReceptorsUfuk Mert0Alshaimaa Adawy1Elisabeth Scharff2Pierre Teichmann3Anna Willms4Verena Haselmann5Cynthia Colmorgen6Johannes Lemke7Silvia von Karstedt8Jürgen Fritsch9Anna Trauzold10Institute for Experimental Cancer Research, University of Kiel, 24105 Kiel, GermanyInstitute for Experimental Cancer Research, University of Kiel, 24105 Kiel, GermanyInstitute for Experimental Cancer Research, University of Kiel, 24105 Kiel, GermanyInstitute for Experimental Cancer Research, University of Kiel, 24105 Kiel, GermanyInstitute for Experimental Cancer Research, University of Kiel, 24105 Kiel, GermanyDepartment of Clinical Chemistry, University Medical Centre, Ruprecht-Karls University of Heidelberg, 68167 Mannheim, GermanyInstitute for Experimental Cancer Research, University of Kiel, 24105 Kiel, GermanyDepartment of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, GermanyDepartment of Translational Genomics, Medical Faculty, University of Cologne, 50931 Cologne, GermanyDepartment of Infection Prevention and Infectious Diseases, University of Regensburg, 93053 Regensburg, GermanyInstitute for Experimental Cancer Research, University of Kiel, 24105 Kiel, GermanyBinding 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.https://www.mdpi.com/2072-6694/11/8/1167TRAILnuclear TRAIL-R1nuclear TRAIL-R2traffickingCRM-1 |
| spellingShingle | Ufuk Mert Alshaimaa Adawy Elisabeth Scharff Pierre Teichmann Anna Willms Verena Haselmann Cynthia Colmorgen Johannes Lemke Silvia von Karstedt Jürgen Fritsch Anna Trauzold TRAIL Induces Nuclear Translocation and Chromatin Localization of TRAIL Death Receptors Cancers TRAIL nuclear TRAIL-R1 nuclear TRAIL-R2 trafficking CRM-1 |
| title | TRAIL Induces Nuclear Translocation and Chromatin Localization of TRAIL Death Receptors |
| title_full | TRAIL Induces Nuclear Translocation and Chromatin Localization of TRAIL Death Receptors |
| title_fullStr | TRAIL Induces Nuclear Translocation and Chromatin Localization of TRAIL Death Receptors |
| title_full_unstemmed | TRAIL Induces Nuclear Translocation and Chromatin Localization of TRAIL Death Receptors |
| title_short | TRAIL Induces Nuclear Translocation and Chromatin Localization of TRAIL Death Receptors |
| title_sort | trail induces nuclear translocation and chromatin localization of trail death receptors |
| topic | TRAIL nuclear TRAIL-R1 nuclear TRAIL-R2 trafficking CRM-1 |
| url | https://www.mdpi.com/2072-6694/11/8/1167 |
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