The human homologue of the yeast polyubiquitination factor Ufd2p is cleaved by caspase 6 and granzyme B during apoptosis

James A. Mahoney, Joseph A. Odin, Sarah M. White, David Shaffer, Andrew Koff, Livia Casciola-Rosen, Antony Rosen

Research output: Contribution to journalArticle

Abstract

In the present study, we demonstrate that a human homologue of Ufd2p (a yeast protein that catalyses the formation of long polyubiquitin chains, and is implicated in responses to environmental stress), UFD2 (ubiquitin fusion degradation protein-2), is cleaved during apoptosis induced by multiple stimuli, including UVB irradiation, Fas ligation, staurosporine treatment and cytotoxic lymphocyte granule-induced death. Caspase 6 and granzyme B efficiently cleave UFD2 [kcat/Km= (4-5)× 104 M-1·S-1] at Asp123, whereas caspases 3 and 7 cleave UFD2 approx. 10-fold less efficiently immediately upstream at Asp109. Thus UFD2 is added to the growing list of proteins with closely spaced caspase and granzyme B cleavage sites, suggesting the presence of a previously unrecognized, conserved motif. Both cleavage sites are contained and conserved within a novel 300-amino-acid N-terminal domain present in apparent UFD2 orthologues in mice and zebrafish, but absent in all UFD2 family members in lower eukaryotes. Full-length recombinant UFD2 exhibited ubiquitin-protein ligase (' E3 ')-like ubiquitination activity in vitro, but this activity was abolished in recombinant UFD2 truncated at the granzyme B/caspase 6 cleavage site. Cleavage of UFD2 by caspases or granzyme B within this putative regulatory N-terminal domain might have important functional consequences within the apoptotic cascade.

Original languageEnglish (US)
Pages (from-to)587-595
Number of pages9
JournalBiochemical Journal
Volume361
Issue number3
DOIs
StatePublished - Feb 1 2002

Keywords

  • Autoantigen
  • Granule pathway
  • Proteasome
  • U box
  • Ubiquitin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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