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TRAIL Induces Nuclear Translocation and Chromatin Localization of TRAIL Death Receptors

Ufuk Mert1, Alshaimaa Adawy1, Elisabeth Scharff1

  • 1Institute for Experimental Cancer Research, University of Kiel, 24105 Kiel, Germany.

Cancers
|August 17, 2019
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors traffic from the cell surface to the nucleus, influencing gene regulation and cancer progression. This novel signaling pathway offers new therapeutic targets for cancer treatment.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Immunology

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binding to its receptors (TRAIL-R1/-R2) on the cell surface was initially explored for cancer therapy.
  • Clinical trials showed disappointing results, with some cancer cells exhibiting TRAIL resistance and TRAIL-R1/-R2 triggering potentially promoting tumor growth.
  • Emerging research highlights intracellular functions of TRAIL receptors, particularly nuclear TRAIL-R2 regulating let-7 maturation, but their nuclear trafficking remains poorly understood.

Purpose of the Study:

  • To investigate the poorly understood mechanism of nuclear trafficking of TRAIL receptors (TRAIL-Rs).
  • To elucidate the origin and regulation of intracellular TRAIL-Rs, specifically nuclear TRAIL-R2.
  • To explore the functional implications of nuclear TRAIL-Rs in cancer biology.

Main Methods:

  • Cell surface biotinylation and intracellular tracking of proteins.
  • Immunoprecipitation and immunofluorescence assays.
  • Analysis of TRAIL-R2 nuclear export sequence (NES) mutants and CRM-1 inhibition using Leptomycin-B.

Main Results:

  • Nuclear TRAIL-Rs originate from the plasma membrane via a TRAIL-dependent, clathrin-dependent endocytosis pathway.
  • Nuclear TRAIL-R2 interacts with Exportin-1/CRM-1, a key protein for nucleo-cytoplasmic transport.
  • Inhibition of CRM-1 or mutation of TRAIL-R2's NES leads to nuclear accumulation of TRAIL-R2.
  • TRAIL-R1 and TRAIL-R2 are constitutively found on chromatin, with TRAIL treatment enhancing this localization.

Conclusions:

  • Surface-activated TRAIL receptors engage in direct trafficking and signaling into the nucleus.
  • This represents a novel signaling paradigm for TNF-superfamily cell surface receptors.
  • Understanding this nuclear trafficking and signaling is crucial for developing new anti-cancer strategies targeting TRAIL pathways.
Keywords:
CRM-1TRAILnuclear TRAIL-R1nuclear TRAIL-R2trafficking

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