HERC6 is the main E3 ligase for global ISG15 conjugation in mouse cells

Diede Oudshoorn, Sander van Boheemen, Maria Teresa Sánchez-Aparicio, Ricardo Rajsbaum Gorodezky, Adolfo García-Sastre, Gijs A. Versteeg

Research output: Contribution to journalArticle

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Abstract

Type I interferon (IFN) stimulates expression and conjugation of the ubiquitin-like modifier IFN-stimulated gene 15 (ISG15), thereby restricting replication of a wide variety of viruses. Conjugation of ISG15 is critical for its antiviral activity in mice. HECT domain and RCC1-like domain containing protein 5 (HerC5) mediates global ISGylation in human cells, whereas its closest relative, HerC6, does not. So far, the requirement of HerC5 for ISG15-mediated antiviral activity has remained unclear. One of the main obstacles to address this issue has been that no HerC5 homologue exists in mice, hampering the generation of a good knock-out model. However, mice do express a homologue of HerC6 that, in contrast to human HerC6, can mediate ISGylation. Here we report that the mouse HerC6 N-terminal RCC1-like domain (RLD) allows ISG15 conjugation when replacing the corresponding domain in the human HerC6 homologue. In addition, sequences in the C-terminal HECT domain of mouse HerC6 also appear to facilitate efficient ISGylation. Mouse HerC6 paralleled human HerC5 in localization and IFN-inducibility. Moreover, HerC6 knock-down in mouse cells abolished global ISGylation, whereas its over expression enhanced the IFNβ promoter and conferred antiviral activity against vesicular stomatitis virus and Newcastle disease virus. Together these data indicate that HerC6 is likely the functional counterpart of human HerC5 in mouse cells, suggesting that HerC6 -/- mice may provide a feasible model to study the role of human HerC5 in antiviral responses.

Original languageEnglish (US)
Article numbere29870
JournalPLoS One
Volume7
Issue number1
DOIs
StatePublished - Jan 17 2012
Externally publishedYes

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Ubiquitin-Protein Ligases
ligases
Antiviral Agents
Genes
Viruses
Interferons
mice
interferons
genes
cells
Interferon Type I
Ubiquitin
Cells
Vesiculovirus
Newcastle disease virus
Vesicular Stomatitis
modifiers (genes)
ubiquitin
Proteins
promoter regions

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Oudshoorn, D., van Boheemen, S., Sánchez-Aparicio, M. T., Rajsbaum Gorodezky, R., García-Sastre, A., & Versteeg, G. A. (2012). HERC6 is the main E3 ligase for global ISG15 conjugation in mouse cells. PLoS One, 7(1), [e29870]. https://doi.org/10.1371/journal.pone.0029870

HERC6 is the main E3 ligase for global ISG15 conjugation in mouse cells. / Oudshoorn, Diede; van Boheemen, Sander; Sánchez-Aparicio, Maria Teresa; Rajsbaum Gorodezky, Ricardo; García-Sastre, Adolfo; Versteeg, Gijs A.

In: PLoS One, Vol. 7, No. 1, e29870, 17.01.2012.

Research output: Contribution to journalArticle

Oudshoorn, D, van Boheemen, S, Sánchez-Aparicio, MT, Rajsbaum Gorodezky, R, García-Sastre, A & Versteeg, GA 2012, 'HERC6 is the main E3 ligase for global ISG15 conjugation in mouse cells', PLoS One, vol. 7, no. 1, e29870. https://doi.org/10.1371/journal.pone.0029870
Oudshoorn D, van Boheemen S, Sánchez-Aparicio MT, Rajsbaum Gorodezky R, García-Sastre A, Versteeg GA. HERC6 is the main E3 ligase for global ISG15 conjugation in mouse cells. PLoS One. 2012 Jan 17;7(1). e29870. https://doi.org/10.1371/journal.pone.0029870
Oudshoorn, Diede ; van Boheemen, Sander ; Sánchez-Aparicio, Maria Teresa ; Rajsbaum Gorodezky, Ricardo ; García-Sastre, Adolfo ; Versteeg, Gijs A. / HERC6 is the main E3 ligase for global ISG15 conjugation in mouse cells. In: PLoS One. 2012 ; Vol. 7, No. 1.
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