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Measuring Composition of CD95 Death-Inducing Signaling Complex and Processing of Procaspase-8 in this Complex
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Apoptotic signalling targets the post-endocytic sorting machinery of the death receptor Fas/CD95

Shruti Sharma1, Antonio Carmona1, Agnieszka Skowronek1

  • 1Department of Biomedical Science & Centre of Membrane Interactions and Dynamics, University of Sheffield, Sheffield, S10 2TN, UK.

Nature Communications
|July 17, 2019
PubMed

Insights

Endosome associated trafficking regulator 1 (ENTR1) controls cell surface Fas levels and apoptosis. ENTR1 cleavage during apoptosis creates a feedback loop, impacting cancer cell death evasion.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Fas receptor is crucial for apoptosis, but cancer cells often evade this by reducing cell surface Fas.
  • The mechanisms behind reduced Fas levels in cancer are not fully understood.

Purpose of the Study:

  • To investigate the role of endosome associated trafficking regulator 1 (ENTR1) in regulating cell surface Fas levels and apoptosis.
  • To elucidate the molecular mechanisms controlling Fas trafficking and signaling termination.

Main Methods:

  • Investigated ENTR1's interaction with Dysbindin.
  • Analyzed the delivery of Fas from endosomes to lysosomes.
  • Examined ENTR1 cleavage during Fas-induced apoptosis.

Main Results:

  • ENTR1 controls cell surface Fas levels by regulating its delivery to lysosomes.
  • ENTR1 binds to Dysbindin to modulate Fas trafficking and signal termination.
  • ENTR1 is cleaved in a caspase-dependent manner during apoptosis, forming a positive feedback loop.

Conclusions:

  • ENTR1 is a key regulator of Fas post-endocytic trafficking and signaling.
  • The interplay between ENTR1 cleavage and endolysosomal trafficking provides a feedback mechanism.
  • Findings offer potential explanations for how cancer cells downregulate death receptors.

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