Abstract | UNLABELLED: The NF-κB signaling pathway plays a critical role in inflammation and innate immunity. Consequently, many viruses have evolved strategies to inhibit NF-κB in order to facilitate replication and evasion of the host immune response. Recently, we determined that ectromelia virus, the causative agent of mousepox, contains a family of four BTB/kelch proteins that interact with cullin-3-based ubiquitin ligases. We demonstrate here that expression of EVM150, one of the four BTB/kelch proteins, inhibited NF-κB activation induced by tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β). Although EVM150 inhibited NF-κB p65 nuclear translocation, IκBα degradation was observed, indicating that EVM150 functioned downstream of IκBα degradation. Significantly, expression of the BTB-only domain of EVM150 blocked NF-κB activation, demonstrating that EVM150 functioned independently of the kelch domain and its role as an adapter for cullin-3-based ubiquitin ligases. Furthermore, cullin-3 knockdown by small interfering RNA demonstrated that cullin-3-based ubiquitin ligases are dispensable for TNF-α-induced NF-κB activation. Interestingly, nuclear translocation of IRF3 and STAT1 still occurred in the presence of EVM150, indicating that EVM150 prevented NF-κB nuclear translocation specifically. In addition to identifying EVM150 as an inhibitor of the NF-κB pathway, this study provides new insights into the role of BTB/kelch proteins during virus infection. IMPORTANCE: With the exception of virulence studies, little work has been done to determine the role of poxviral BTB/kelch proteins during infection. This study, for the first time, has identified a mechanism for the ectromelia virus BTB/kelch protein EVM150. Here, we show that EVM150 is a novel inhibitor of the cellular NF-κB pathway, an important component of the antiviral response. This study adds EVM150 to the growing list of NF-κB inhibitors in poxviruses and provides new insights into the role of BTB/kelch proteins during virus infection.
|
Authors | Qian Wang, Kristin Burles, Brianne Couturier, Crystal M H Randall, Joanna Shisler, Michele Barry |
Journal | Journal of virology
(J Virol)
Vol. 88
Issue 9
Pg. 4853-65
(May 2014)
ISSN: 1098-5514 [Electronic] United States |
PMID | 24522926
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Interleukin-1beta
- NF-kappa B
- Tumor Necrosis Factor-alpha
- Viral Proteins
|
Topics |
- Animals
- Cell Line
- Ectromelia virus
(immunology)
- Host-Pathogen Interactions
- Humans
- Immune Evasion
- Interleukin-1beta
(immunology)
- NF-kappa B
(antagonists & inhibitors)
- Signal Transduction
- Tumor Necrosis Factor-alpha
(immunology)
- Viral Proteins
(genetics, metabolism)
|