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Identification of a ligand for the death-domain-containing receptor Apo3

S A Marsters1, J P Sheridan, R M Pitti

  • 1Department of Molecular Oncology Genentech Inc 1 DNA Way, South San Francisco, California, 94080-4918, USA.

Current Biology : CB
|May 20, 1998
PubMed

Insights

Researchers discovered a new tumor necrosis factor (TNF) relative, Apo3 ligand (Apo3L), which activates apoptosis and NF-kappaB signaling pathways. Apo3L is expressed in many tissues, indicating broader immune system roles than previously understood.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • The tumor necrosis factor (TNF) cytokine family is crucial for immune system regulation, influencing gene transcription and apoptosis.
  • TNF is primarily produced by activated lymphocytes and macrophages, mediating cellular responses.
  • A novel TNF relative, Apo3 ligand (Apo3L), has been identified, binding to the Apo3 receptor (also known as DR3, WSL-1, TRAMP, or LARD).

Purpose of the Study:

  • To characterize the novel Apo3 ligand (Apo3L) and its biological functions.
  • To investigate the signaling pathways activated by Apo3L and its relationship to TNF.
  • To determine the tissue distribution and genetic location of Apo3L.

Main Methods:

  • Sequence analysis to determine Apo3L identity and transmembrane protein nature.
  • mRNA detection across various human tissues to assess tissue distribution.
  • Gene mapping to identify the chromosomal location of Apo3L.
  • Functional assays using soluble Apo3L to induce apoptosis and NF-kappaB activation in human cell lines.
  • Inhibition studies using caspase inhibitors and dominant-negative mutants (FADD/MORT1, TNF signaling factors) to elucidate signaling pathways.

Main Results:

  • Apo3L is a 249 amino-acid type II transmembrane protein with significant sequence homology to TNF.
  • Apo3L mRNA is detected in numerous human tissues, and its gene is mapped to chromosome 17p13.
  • Soluble Apo3L induces apoptosis and NF-kappaB activation in human cell lines.
  • Apo3L-induced apoptosis is blocked by caspase inhibitors and a dominant-negative FADD/MORT1 mutant.
  • NF-kappaB activation by Apo3L is inhibited by dominant-negative mutants of key TNF signaling factors.
  • Apo3L exhibits a much wider tissue distribution compared to TNF.

Conclusions:

  • Apo3L represents a novel member of the TNF cytokine family with distinct expression patterns.
  • Apo3L shares overlapping signaling functions with TNF, including the induction of apoptosis and NF-kappaB activation.
  • The signaling pathways for Apo3L-induced apoptosis and NF-kappaB activation involve components shared with TNF signaling, such as FADD/MORT1.
  • The broad tissue distribution of Apo3L suggests a significant and widespread role in immune system regulation and other biological processes.

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