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FAN, a novel WD-repeat protein, couples the p55 TNF-receptor to neutral sphingomyelinase

S Adam-Klages1, D Adam, K Wiegmann

  • 1Institut für Immunologie, Christian-Albrechts-Universität Kiel, Federal Republic of Germany.

Cell
|September 20, 1996
PubMed

Insights

Researchers identified FAN, a novel protein that binds to the tumor necrosis factor-receptor (TNF-R55). FAN regulates ceramide production via neutral sphingomyelinase (N-SMase), a key step in TNF signaling pathways.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Biochemistry

Background:

  • Intracellular signaling initiated by the 55 kDa tumor necrosis factor-receptor (TNF-R55) involves protein intermediates interacting with its cytoplasmic domains.
  • A specific nine amino acid motif within TNF-R55's cytoplasmic region is crucial for activating neutral sphingomyelinase (N-SMase).

Purpose of the Study:

  • To identify novel protein intermediates involved in TNF-R55 signaling.
  • To elucidate the role of these intermediates in the activation of N-SMase and subsequent signaling events.

Main Methods:

  • Utilized the yeast interaction trap system to screen for interacting proteins.
  • Employed a peptide scanning library to identify binding motifs.
  • Investigated the effect of FAN protein expression (full-length and mutants) on N-SMase activity in TNF-treated cells.

Main Results:

  • Identified a novel WD-repeat protein, termed FAN, that specifically binds to the nine amino acid motif on TNF-R55.
  • Overexpression of full-length FAN enhanced N-SMase activity in cells stimulated with TNF.
  • Truncated FAN mutants exhibited dominant negative effects, inhibiting N-SMase activity.

Conclusions:

  • FAN acts as a crucial regulator in TNF-R55-mediated intracellular signaling.
  • FAN's interaction with TNF-R55 modulates N-SMase activity, impacting ceramide production and TNF signaling pathways.

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