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A novel class of viral Ankyrin proteins targeting the host E3 ubiquitin ligase Cullin-2

Odon, Valerie, Georgana, Iliana, Holley, Joe, Morata, Jordi and Maluquer de Motes, Carlos (2018) A novel class of viral Ankyrin proteins targeting the host E3 ubiquitin ligase Cullin-2 Journal of Virology.

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Ankyrin repeat (ANK) domains are one of the most abundant motifs in eukaryotic proteins. ANK proteins are rare amongst viruses with the exception of poxviruses, which presumably acquired them from the host via horizontal gene transfer. The architecture of poxvirus ANK proteins is however different from their cellular counterparts and this precludes a direct acquisition event. Here we combine bioinformatics analysis and quantitative proteomics to discover a new class of viral ANK proteins with a domain organisation that relates to cellular ANK proteins. These non-canonical viral ANK proteins, termed ANK/BC, interact with host Cullin-2 via a C-terminal BC box resembling that of cellular Cullin-2 substrate adaptors such as the von Hippel-Lindau protein. Mutagenesis of the BC box-like sequence abrogates binding to Cullin-2, whereas fusion of this motif to an ANK-only protein confers Cullin-2 association. We demonstrate that these viral ANK/BC proteins are potent immunomodulatory proteins suppressing the activation of the pro-inflammatory transcription factors NF-κB and IRF-3 and the production of cytokines and chemokines including interferon, and that association with Cullin-2 is required for optimal inhibitory activity. ANK/BC proteins exist in several orthopoxviruses and cluster into 2 closely related orthologue groups in a phylogenetic lineage that is separate from canonical ANK/F-box proteins. Given the existence of cellular proteins with similar architecture, viral ANK/BC proteins may be closely related to the original ANK gene acquired by an ancestral orthopoxvirus. These findings uncover a novel viral strategy to antagonise innate immunity and shed light on the origin of the poxviral ANK protein family.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
Morata, Jordi
Maluquer de Motes,
Date : 26 September 2018
DOI : 10.1128/JVI.01374-18
Copyright Disclaimer : Copyright © 2018 Odon et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Depositing User : Melanie Hughes
Date Deposited : 26 Sep 2018 12:51
Last Modified : 30 Nov 2018 17:40

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