TRAIL Induces Nuclear Translocation and Chromatin Localization of TRAIL Death Receptors
AbstractBinding 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
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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.
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(8):1167.Chicago/Turabian Style
Mert, Ufuk; Adawy, Alshaimaa; Scharff, Elisabeth; Teichmann, Pierre; Willms, Anna; Haselmann, Verena; Colmorgen, Cynthia; Lemke, Johannes; von Karstedt, Silvia; Fritsch, Jürgen; Trauzold, Anna. 2019. "TRAIL Induces Nuclear Translocation and Chromatin Localization of TRAIL Death Receptors." Cancers 11, no. 8: 1167.
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