Death Receptor Recruitment of Endogenous Caspase-10 and Apoptosis Initiation in the Absence of Caspase-8

Frank C. Kischkel, David A. Lawrence, Antoine Tinel, Heidi LeBlanc, Arvind Virmani, Peter Schow, Adi Gazdar, John Blenis, David Arnott, Avi Ashkenazi

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398 Scopus citations

Abstract

Caspase-8 is believed to play an obligatory role in apoptosis initiation by death receptors, but the role of its structural relative, caspase-10, remains controversial. Although earlier evidence implicated caspase-10 in apoptosis signaling by CD95L and Apo2L/TRAIL, recent studies indicated that these death receptor ligands recruit caspase-8 but not caspase-10 to their death-inducing signaling complex (DISC) even in presence of abundant caspase-10. We characterized a series of caspase-10-specific antibodies and found that certain commercially available antibodies cross-react with HSP60, shedding new light on previous results. The majority of 55 lung and breast carcinoma cell lines expressed mRNA for both caspase-8 and -10; however, immunoblot analysis revealed that caspase-10 protein expression was more frequently absent than that of caspase-8, suggesting a possible selective pressure against caspase-10 production in cancer cells. In nontransfected cells expressing both caspases, CD95L and Apo2L/TRAIL recruited endogenous caspase-10 as well as caspase-8 to their DISC, where both enzymes were proteolytically processed with similar kinetics. Caspase-10 recruitment required the adaptor FADD/Mort1, and caspase-10 cleavage in vitro required DISC assembly, consistent with the processing of an apoptosis initiator. Cells expressing only one of the caspases underwent ligand-induced apoptosis, indicating that each caspase can initiate apoptosis independently of the other. Thus, apoptosis signaling by death receptors involves not only caspase-8 but also caspase-10, and both caspases may have equally important roles in apoptosis initiation.

Original languageEnglish (US)
Pages (from-to)46639-46646
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number49
DOIs
StatePublished - Dec 7 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Kischkel, F. C., Lawrence, D. A., Tinel, A., LeBlanc, H., Virmani, A., Schow, P., Gazdar, A., Blenis, J., Arnott, D., & Ashkenazi, A. (2001). Death Receptor Recruitment of Endogenous Caspase-10 and Apoptosis Initiation in the Absence of Caspase-8. Journal of Biological Chemistry, 276(49), 46639-46646. https://doi.org/10.1074/jbc.M105102200