Novel class of viral ankyrin proteins targeting the host E3 ubiquitin ligase Cullin-2
Odon, Valerie (University of Surrey. Department of Microbial Sciences)
Georgana, Iliana (University of Surrey. Department of Microbial Sciences)
Holley, Joe (University of Surrey. Department of Microbial Sciences)
Morata, Jordi (Centre de Recerca en Agrigenòmica)
Maluquer De Motes, Carlos (University of Surrey. Department of Microbial Sciences)

Data:	2018
Resum:	Ankyrin repeat (ANK) domains are among 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 that of 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 organization that relates to cellular ANK proteins. These noncanonical 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 demonstrated that these viral ANK/BC proteins are potent immunomodulatory proteins suppressing the activation of the proinflammatory transcription factors NF-B and interferon (IFN)-responsive factor 3 (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 that of 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 antagonize innate immunity and shed light on the origin of the poxviral ANK protein family.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Ankyrin proteins ; Cullin ubiquitin system ; Immune evasion ; Poxvirus
Publicat a:	Journal of Virology, Vol. 92, Issue 23 (December 2018) , art. e01374, ISSN 1098-5514

DOI: 10.1128/JVI.01374-18
PMID: 30258003

15 p, 2.1 MB

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