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...

Full description

Saved in:
Bibliographic Details
Published in:Cancers 2019-08, Vol.11 (8), p.1167
Main Authors: Mert, Ufuk, Adawy, Alshaimaa, Scharff, Elisabeth, Teichmann, Pierre, Willms, Anna, Haselmann, Verena, Colmorgen, Cynthia, Lemke, Johannes, von Karstedt, Silvia, Fritsch, Jürgen, Trauzold, Anna
Format: Article
Language:English
Subjects:
Apoptosis
Biotinylation
Breast cancer
Cell surface
Chromatin
Clathrin
Clinical trials
Cytoplasm
Death receptors
Endocytosis
Immunofluorescence
Immunoprecipitation
Intracellular
Kinases
Ligands
Localization
Membrane trafficking
Metastasis
Nuclear transport
Plasma
Proteins
TRAIL protein
Tumor cells
Tumor necrosis factor
Tumor necrosis factor-TNF
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers11081167