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Dugbe virus ovarian tumour domain interferes with ubiquitin/ISG15-regulated innate immune cell signalling

S Bakshi1,2, B Holzer1, A Bridgen2

  • 1Institute for Animal Health, Ash Road, Pirbright, Surrey GU24 0NF, UK.

The Journal of General Virology
|November 9, 2012
PubMed

Insights

The nairovirus OTU domain removes ubiquitin and ISG15, effectively blocking TNF-α/NF-κB and interferon/JAK/STAT signaling. This enzymatic activity is crucial for inhibiting these pathways, though substrate binding persists even in inactive mutants.

Area of Science:

  • Virology
  • Molecular Biology
  • Cellular Signalling

Background:

  • Nairovirus L protein possesses an ovarian tumour (OTU) domain with deubiquitinating and deISGylating activity.
  • This activity is predicted to influence host cell signalling pathways.

Purpose of the Study:

  • To confirm the deubiquitinating and deISGylating activity of the Dugbe virus OTU domain.
  • To investigate the impact of this activity on TNF-α/NF-κB and interferon/JAK/STAT signalling pathways.
  • To elucidate the role of the catalytic site in these inhibitory effects.

Main Methods:

  • Expression of the Dugbe virus OTU domain in cells.
  • Introduction of point mutations in the catalytic site (C40A, H151A, double mutant).
  • Assessment of deubiquitination and deISGylation activity.
  • Analysis of TNF-α/NF-κB and interferon/JAK/STAT pathway activation.
  • Subcellular localization studies by expressing mutated OTU domains.

Main Results:

  • The Dugbe virus OTU domain exhibits significant deubiquitinating and deISGylating activity.
  • The OTU domain effectively blocks TNF-α/NF-κB and interferon/JAK/STAT signalling pathways.
  • Mutations in the catalytic site abolish enzymatic activity and reduce pathway inhibition.
  • Inactive OTU mutants retain substrate binding capability.
  • Nuclear localization of the OTU domain is required for blocking TNF-α-induced NF-κB activation, but not for blocking type I interferon signalling.

Conclusions:

  • The enzymatic activity of the nairovirus OTU domain is essential for blocking TNF-α/NF-κB and interferon/JAK/STAT signalling.
  • Substrate binding by the OTU domain can occur independently of its catalytic activity.
  • The subcellular localization of the OTU domain influences its specific inhibitory effects on distinct signalling pathways.

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