Ectromelia virus encodes a BTB/kelch protein, EVM150, that inhibits NF-κB signaling.

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)