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Subcellular compartmentalization of TNF receptor-1 and CD95 signaling pathways

Vladimir Tchikov1, Uwe Bertsch, Jürgen Fritsch

  • 1Institute of Immunology, Christian-Albrechts-University Kiel, Michaelisstr. 5, D-24105 Kiel, Germany.

European Journal of Cell Biology
|December 15, 2010
PubMed

Insights

Death receptors like TNF-R1 and CD95 can trigger cell death or survival. Receptor internalization and trafficking control these signals, influencing cell fate and potentially impacting viral strategies.

Area of Science:

  • Cell biology
  • Molecular signaling
  • Immunology

Background:

  • Death receptors (TNF-R1, CD95, TRAIL receptors) mediate opposing cellular outcomes: apoptosis or survival signals via NF-κB and MAPK/ERK.
  • Receptor internalization and intracellular trafficking are emerging as key regulators of these distinct signaling pathways.
  • Understanding how receptor trafficking dictates cell fate is crucial for deciphering complex biological phenomena.

Purpose of the Study:

  • To review findings on the compartmentalization of TNF receptor-1 (TNF-R1) and CD95 signaling within the Collaborative Research Center 415 (CRC 415).
  • To elucidate the role of receptor internalization in determining the signaling outcome (apoptosis vs. survival).
  • To highlight novel molecular players and mechanisms involved in TNF-R1 and CD95-mediated signaling.

Main Methods:

  • Investigated the role of receptor internalization and intracellular trafficking in TNF-R1 and CD95 signaling.
  • Examined the fusion of internalized TNF-receptosomes with trans-Golgi vesicles.
  • Analyzed the involvement of acid sphingomyelinase, ceramide, cathepsin D, and endosomal E3-ubiquitin ligases (CARP-2, CARP-1).

Main Results:

  • Receptor internalization critically determines whether TNF-R1 and CD95 initiate apoptosis or survival signals.
  • Fusion of TNF-receptosomes with trans-Golgi vesicles represents a novel pathway for death signal transduction.
  • Acid sphingomyelinase, ceramide, cathepsin D, and CARP-2/CARP-1 are identified as key regulators in cell death and NF-κB signaling.
  • Adenoviruses impede TNF-R1 internalization to evade host cell apoptosis, demonstrating the biological significance of receptor compartmentalization.

Conclusions:

  • Receptor internalization and intracellular trafficking are crucial for selective signal transduction by death receptors.
  • Compartmentalization of TNF-R1 and CD95 signaling via endosomal trafficking dictates cell fate.
  • Novel molecular players like ceramide and cathepsin D contribute to the cell death pathway, while endosomal E3 ligases regulate NF-κB signaling.

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