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Compartmentalization of TNF receptor 1 signaling: internalized TNF receptosomes as death signaling vesicles

Wulf Schneider-Brachert1, Vladimir Tchikov, Jens Neumeyer

  • 1Institute of Medical Microbiology and Hygiene, University of Regensburg, D-93053, Germany.

Immunity
|September 11, 2004
PubMed

Insights

Internalization of TNF-R1 (Tumor Necrosis Factor Receptor 1) is crucial for forming the death-inducing signaling complex (DISC) and initiating apoptosis. This process involves receptor endocytosis, essential for DISC assembly and subsequent cell death signaling.

Area of Science:

  • Molecular biology
  • Cell signaling
  • Immunology

Background:

  • The molecular mechanisms governing initial signaling complex assembly at the Tumor Necrosis Factor Receptor 1 (TNF-R1) are not well understood.
  • Tumor Necrosis Factor Receptor 1 (TNF-R1) plays a critical role in inflammatory and apoptotic pathways.

Purpose of the Study:

  • To elucidate the molecular regulation of signaling complex recruitment to TNF-R1.
  • To investigate the role of TNF-R1 internalization in the formation of the death-inducing signaling complex (DISC) and subsequent apoptosis.

Main Methods:

  • Utilized cell lines expressing wild-type and internalization-deficient TNF-R1 mutants (TNF-R1 DeltaTRID).
  • Investigated the recruitment dynamics of signaling molecules (TRADD, FADD, caspase-8, RIP-1, TRAF-2) to TNF-R1 at different cellular locations (plasma membrane vs. endosomes).
  • Analyzed the functional consequences of TNF-R1 internalization on DISC formation, apoptosis, and activation of downstream enzymes (acid sphingomyelinase, cathepsin D).

Main Results:

  • Internalized TNF-R1 (TNF receptosomes) rapidly recruits TRADD, FADD, and caspase-8 to form the DISC.
  • TNF-R1 internalization, mediated by the TNF-R1 internalization domain (TRID), is essential for DISC formation and apoptosis.
  • Recruitment of RIP-1 and TRAF-2 occurs at the plasma membrane, while DISC assembly is dependent on receptor endocytosis.
  • Fusion of TNF receptosomes with trans-Golgi vesicles activates acid sphingomyelinase and cathepsin D, indicating compartmentalization of signaling pathways.

Conclusions:

  • TNF-R1 internalization is an inseparable event from DISC formation and apoptosis.
  • Receptor endocytosis is critical for the assembly of the TNF-R1-associated DISC.
  • TNF receptosomes compartmentalize signaling pathways by segregating plasma membrane-derived endocytic vesicles, thereby regulating TNF-mediated cellular responses.

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