CLARP, a death effector domain-containing protein interacts with caspase-8 and regulates apoptosis

Naohiro Inohara, Takeyoshi Koseki, Yuanming Hu, Shu Chen, Gabriel Núñez

Research output: Contribution to journalArticle

260 Citations (Scopus)

Abstract

We have identified and characterized CLARP, a caspase-like apoptosis- regulatory protein. Sequence analysis revealed that human CLARP contains two amino-terminal death effector domains fused to a carboxyl-terminal caspase- like domain. The structure and amino acid sequence of CLARP resemble those of caspase-8, caspase-10, and DCP2, a Drosophila melanogaster protein identified in this study. Unlike caspase-8, caspase-10, and DCP2, however, two important residues predicted to be involved in catalysis were lost in the caspase-like domain of CLARP. Analysis with fluorogenic substrates for caspase activity confirmed that CLARP is catalytically inactive. CLARP was found to interact with caspase-8 but not with FADD/MORT-1, an upstream death effector domain- containing protein of the Fas and tumor necrosis factor receptor 1 signaling pathway. Expression of CLARP induced apoptosis, which was blocked by the viral caspase inhibitor p35, dominant negative mutant caspase-8, and the synthetic caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-(OMe)- fluoromethylketone (zVAD-fmk). Moreover, CLARP augmented the killing ability of caspase-8 and FADD/MORT-1 in mammalian cells. The human clarp gene maps to 2q33. Thus, CLARP represents a regulator of the upstream caspase-8, which may play a role in apoptosis during tissue development and homeostasis.

Original languageEnglish
Pages (from-to)10717-10722
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number20
DOIs
Publication statusPublished - 1997 Sep 30
Externally publishedYes

ASJC Scopus subject areas

  • General

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