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

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 [k(cat)/K(m)=(4-5) x 10(4) M(-1) x s(-1)] at Asp(123), whereas caspases 3 and 7 cleave UFD2 approx. 10-fold less efficiently immediately upstream at Asp(109). 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.

Pubmed ID: 11802788


  • Mahoney JA
  • Odin JA
  • White SM
  • Shaffer D
  • Koff A
  • Casciola-Rosen L
  • Rosen A


The Biochemical journal

Publication Data

February 1, 2002

Associated Grants

  • Agency: NIAMS NIH HHS, Id: AR44684
  • Agency: NIDCR NIH HHS, Id: DE12354
  • Agency: NIGMS NIH HHS, Id: GM52597
  • Agency: NIDDK NIH HHS, Id: T32DK07832

Mesh Terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Apoptosis
  • Baculoviridae
  • Binding Sites
  • Blotting, Northern
  • Caspase 6
  • Caspases
  • Cloning, Molecular
  • Enzyme Inhibitors
  • Fungal Proteins
  • Granzymes
  • HeLa Cells
  • Humans
  • Kinetics
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Precipitin Tests
  • Protein Binding
  • Protein Structure, Tertiary
  • Recombinant Proteins
  • Saccharomyces cerevisiae Proteins
  • Sequence Homology, Amino Acid
  • Serine Endopeptidases
  • Staurosporine
  • Tissue Distribution
  • Ubiquitin
  • Ubiquitin-Conjugating Enzymes
  • Ultraviolet Rays