Myxoma Virus M11L Blocks Apoptosis through Inhibition of Conformational Activation of Bax at the Mitochondria
Bibliographic record
Abstract
Many viruses inhibit or retard apoptosis, a strategy that subverts one of the most ancient antiviral mechanisms. M11L, a myxoma virus-encoded antiapoptotic protein, has been previously shown to localize to mitochondria and block apoptosis of virus-infected cells (H. Everett, M. Barry, S. F. Lee, X. J. Sun, K. Graham, J. Stone, R. C. Bleackley, and G. McFadden, J. Exp. Med. 191:1487-1498, 2000; H. Everett, M. Barry, X. Sun, S. F. Lee, C. Frantz, L. G. Berthiaume, G. McFadden, and R. C. Bleackley, J. Exp. Med. 196:1127-1139, 2002; and G. Wang, J. W. Barrett, S. H. Nazarian, H. Everett, X. Gao, C. Bleackley, K. Colwill, M. F. Moran, and G. McFadden, J. Virol. 78:7097-7111, 2004). This protection from apoptosis involves constitutive-forming inhibitory complexes with the peripheral benzodiazepine receptor and Bak on the outer mitochondrial membrane. Here, we extend the study to investigate the interference of M11L with Bax activation during the process of apoptosis. Myxoma virus infection triggers an early apoptotic signal that induces rapid Bax translocation from cytoplasm to mitochondria, despite the existence of various viral antiapoptotic proteins. However, in the presence of M11L, the structural activation of Bax at the mitochondrial membrane, which is characterized by the occurrence of a Bax conformational change, is blocked in both M11L-expressing myxoma-infected cells and M11L-transfected cells under apoptotic stimulation. In addition, inducible binding of M11L to the mitochondrially localized Bax is detected in myxoma virus-infected cells and in M11L/Bax-cotransfected cells as measured by immunoprecipitation and tandem affinity purification analysis, respectively. Importantly, this inducible Bax/M11L interaction is independent of Bak, demonstrated by the complete block of Bax-mediated apoptosis in myxoma-infected cells that lack Bak expression. Our findings reveal that myxoma M11L modulates apoptosis by multiple independent strategies which all contribute to the blockade of apoptosis at the mitochondrial checkpoint.
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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 | 0.000 | 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) | 0.000 | 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 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".