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Caspase 7 can cleave tumor necrosis factor receptor-I (p60) at a non-consensus motif, in vitro

D W Ethell1, E Bossy-Wetzel, D E Bredesen

  • 1Program in Aging, The Burnham Institute, La Jolla, CA 92037, USA. dethell@liai.org

Biochimica Et Biophysica Acta
|January 5, 2002
PubMed

Insights

Tumor necrosis factor receptor-I (TNFRI) is degraded during apoptosis. Caspase 7, not caspase 8, cleaves TNFRI at a novel site, suggesting broader caspase specificity.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Tumor necrosis factor receptor-I (TNFRI) signaling can initiate cell survival or apoptosis.
  • TNFRI interacts with TRAF2, RIP, TRADD, FADD/MORT1, and procaspase-8 to form a death-inducing signaling complex.
  • TNFRI undergoes caspase-dependent degradation during apoptosis.

Purpose of the Study:

  • To investigate the specific caspase responsible for TNFRI cleavage during apoptosis.
  • To identify and characterize the cleavage site on TNFRI.
  • To determine the substrate specificity of caspases involved in TNFRI degradation.

Main Methods:

  • In vitro caspase cleavage assays using purified caspases and TNFRI.
  • Site-directed mutagenesis to alter potential caspase cleavage sites.
  • Analysis of TNFRI cleavage products during apoptosis.

Main Results:

  • Human TNFRI is cleaved in a caspase-dependent manner during apoptosis.
  • Caspase 7, but not caspase 8, directly cleaved TNFRI in vitro.
  • A novel cleavage motif (GELE) was identified, distinct from canonical caspase recognition sites.
  • Mutation of the identified cleavage site abolished TNFRI degradation during apoptosis.

Conclusions:

  • Caspase 7 plays a direct role in the degradation of TNFRI during apoptosis.
  • The cleavage of TNFRI by caspase 7 expands the known substrate specificity of caspases.
  • This finding suggests that caspases may have a broader range of targets than previously understood.

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