Herpesvirus deconjugases inhibit the IFN response by promoting TRIM25 autoubiquitination and functional inactivation of the RIG-I signalosome

Soham Gupta, PaÈ ivi YlaÈ-Anttila1, Simone Callegari, Ming-Han Tsai, Henri-Jacques Delecluse, Maria G. Masucci. PLoS Pathog. (2018) 14(1):e1006852.

Abstract

The N-terminal domains of herpesvirus large tegument proteins exhibit a conserved ubiquitin deconjugase activity and play important roles in counteracting host innate immunity.^{1, 2} However, studies exploring the precise counteracting mechanisms and target proteins are hampered by the difficulty to express these deconjugases with such large protein sizes. By utilizing the N-terminal catalytic domain alone of EBV deconjugase BPLF1 as a bait, the authors identified several members of the 14-3-3 protein family as major BPLF1-binding partners. Further analysis revealed that an E3 ubiquitin ligase TRIM25 forms a tri-molecule complex with BPLF1 and 14-3-3. Following previous clues that both 14-3-3 and TRIM25 promote K63-linked ubiquitination of RIG-I and RIG-I-mediated signaling³, the authors demonstrated that BPLF1 inhibits RIG-I-mediated interferon response including IRF3 activation and induction of interferon and interferon-stimulated genes. The deconjugase activity of BPLF1 is not involved in the tri-molecule interaction but is required for inhibition of RIG-I signaling. Depending on its deconjugase activity, BPLF1 promotes autoubiquitination and dimerization of TRIM25 but reduces K63-linked ubiquitination of RIG-I, which may account for the suppression of RIG-I-mediated signaling. Moreover, interaction with TRIM25 and 14-3-3 and reduction of RIG-I ubiquitination are conserved among all herpesvirus deconjugases tested. Therefore, this finding may be useful for developing a novel anti-viral treatment against a broad spectrum of herpesviruses.

References

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