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HERC5 is an IFN-induced HECT-type E3 protein ligase that mediates type I IFN-induced ISGylation of protein targets.

Type I IFNs induce the expression of IFN-stimulated gene 15 (ISG15) and its conjugation to cellular targets. ISGylation is a multistep process involving IFN-inducible Ube1L, UbcH8, and a yet-to-be identified E3 ligase. Here we report the identification of an IFN-induced HECT-type E3 protein ligase, HERC5/Ceb1, which mediates ISGylation. We also defined a number of proteins modified by ISG15 after IFN triggering or HERC5 overexpression. A reduction in endogenous HERC5 by small interfering RNA inhibition blocks the IFN-induced ISG15 conjugation. Conversely, HERC5 coexpression with Ube1L and UbcH8 induces the ISG15 conjugation in vivo independent of IFN stimulation. A targeted substitution of Cys-994 to Ala in the HECT domain of HERC5 completely abrogates its E3 protein ligase activity. Therefore, this study demonstrates that HERC5/Ceb1 is involved in the conjugation of ISG15 to cellular proteins.

Pubmed ID: 16815975


  • Wong JJ
  • Pung YF
  • Sze NS
  • Chin KC


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

July 11, 2006

Associated Grants


Mesh Terms

  • Cell Line
  • Cytokines
  • HeLa Cells
  • Humans
  • Interferon Type I
  • Intracellular Signaling Peptides and Proteins
  • Proteins
  • RNA Interference
  • Ubiquitin-Protein Ligases
  • Ubiquitins