The vaccinia virus protein, C16, promotes the ubiquitylation and relocalization of the antiviral E3 ubiquitin-ligase, TRIM25
Bibliographic record
Abstract
Poxviruses co-opt the ubiquitin (Ub)-proteasome system (UPS) to facilitate virus replication, evade the innate immune response, and block programmed cell death of infected cells. Moreover, the UPS is an integral component of innate immune signaling pathways used by the host to respond to infection. To further elucidate how the UPS is engaged early during poxvirus infection, we quantified viral and cellular peptides with a Ub remnant motif (diGly peptides) from lysates of uninfected and vaccinia virus Copenhagen strain (VACV-Cop)-infected HeLa cells. Of note, we identified several ubiquitylated peptides from the cellular antiviral protein, TRIM25, that were enriched for, or exclusively found, in VACV-Cop-infected cells. TRIM25 is an E3 ligase for Ub and the Ub-like protein, ISG15, and TRIM25 performs several functions including activating the type I interferon response. Higher-molecular weight, ubiquitylated TRIM25 species were evident as early as 1 h post-infection of HeLa cells with VACV-Cop, and they persisted throughout infection. Proteasomal or lysosomal degradation did not appear to be a major consequence of this ubiquitylation; however, TRIM25 ubiquitylation correlated with its relocalization to punctate structures in infected cells. C16, a Bcl-2 family-like protein encoded by identical genes on both arms of the VACV-Cop genome, was both necessary and sufficient to promote TRIM25 ubiquitylation and relocalization. These phenomena were not evident in cells infected with Orthopoxviruses lacking the genes encoding for C16. We postulate that the ubiquitylation and/or relocalization of TRIM25 induced by C16 could represent a novel mechanism for poxviruses to subvert the host antiviral response.IMPORTANCEUbiquitylation is a versatile post-translational modification that is required for poxviruses to replicate their genomes and evade host cell defenses to infection. At the same time, both degradative and non-degradative protein ubiquitylation are critical components of the innate and adaptive immune responses to infection. In this study, we opted for a proteomics approach to examine changes in protein ubiquitylation early after vaccinia virus infection with the goal of identifying novel ways by which ubiquitylation is exploited during infection. We demonstrate that many Orthopoxviruses utilize the Bcl-2 family-like protein C16 to promote the ubiquitylation and relocalization of the cellular E3 ubiquitin/ISG15-ligase, TRIM25, which we hypothesize represents a novel strategy by which these viruses evade the host cell antiviral response. Moreover, our findings hint that Orthopoxviruses may also have C16-independent strategies to interfere with the function of TRIM25.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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 source (direct Gemma or distilled Codex), 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".