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Prevention of constitutive TNF receptor 1 signaling by silencer of death domains

Y Jiang1, J D Woronicz, W Liu

  • 1Tularik, Two Corporate Drive, South San Francisco, CA 94080, USA.

Science (New York, N.Y.)
|January 23, 1999
PubMed

Insights

Silencer of death domains (SODD) protein prevents spontaneous signaling by TNF-R1. TNF signaling releases SODD, allowing receptor activation and downstream NF-kappaB or apoptosis pathways.

Area of Science:

  • Cellular Biology
  • Molecular Signaling
  • Immunology

Background:

  • Tumor necrosis factor receptor type 1 (TNF-R1) mediates crucial cellular responses like apoptosis and NF-kappaB activation.
  • These signals normally require TNF-induced receptor aggregation for initiation.
  • Overexpressed TNF-R1 can signal independently of ligand, suggesting a regulatory mechanism is involved.

Purpose of the Study:

  • To investigate the mechanism preventing spontaneous TNF-R1 signaling.
  • To identify proteins associated with TNF-R1's death domain.
  • To elucidate the role of these proteins in regulating TNF receptor signaling.

Main Methods:

  • Co-immunoprecipitation assays to detect protein-protein interactions.
  • Western blotting to analyze protein expression and release.
  • Studies on overexpressed TNF-R1 and its interaction with SODD.

Main Results:

  • Silencer of death domains (SODD) was found associated with the TNF-R1 death domain.
  • TNF treatment induced the release of SODD from TNF-R1.
  • SODD also interacts with death receptor-3 (DR3), indicating a broader role.

Conclusions:

  • SODD acts as a critical inhibitor of spontaneous TNF-R1 signaling.
  • TNF-mediated release of SODD is essential for receptor activation.
  • SODD association represents a general mechanism for regulating death domain-containing receptors.

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