Ectromelia Virus Encodes a BTB/kelch Protein, EVM150, That Inhibits NF-κB Signaling
Bibliographic record
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".