Activation and Evasion of the FEAR Pathway by RNA Viruses
Bibliographic record
Abstract
). The human FEAR pathway is mediated by the FACT complex, consisting of hSpt16 and SSRP1 subunits, that remodels chromatin to activate expression of the antiviral transcription factor, ETS-1. To counter this pathway, poxvirus A51R proteins tether SUMOylated hSpt16 subunits to microtubules to prevent ETS-1 expression. While these observations indicate a role for the FEAR pathway in DNA virus restriction, it was unclear if RNA viruses interact with this pathway. Here, we show that RNA viruses are also restricted by the FEAR pathway, yet encode mechanisms distinct from poxviruses to counter this response. We show vesicular stomatitis virus (VSV), a rhabdovirus, utilizes its matrix (M) protein to promote proteasome-dependent degradation of SUMOylated hSpt16 and to block ETS-1 nuclear import. Strains encoding mutant M proteins that cannot antagonize the FEAR pathway exhibit replication defects in human cells that can be rescued by hSpt16 or ETS-1 depletion. Moreover, FACT inhibitor treatment enhanced the replication of oncolytic VSV strains encoding defective M proteins in restrictive cancer cells, suggesting FEAR pathway inhibition may improve oncolytic virotherapy. Strikingly, we provide evidence that the inability of VSV M to degrade SUMOylated Spt16 in lepidopteran insect cells results in abortive infection, suggesting VSV-Spt16 interactions influence virus host range. Lastly, we show that human and murine paramyxovirus target SUMOylated Spt16 proteins for degradation in human and murine cells utilizing a conserved N-terminal motif in their accessory "C" proteins. Collectively, our study illustrates that DNA and RNA viruses have independently evolved diverse mechanisms to antagonize SUMOylated host Spt16 proteins, underscoring the physiological importance of the FEAR pathway to antiviral immunity.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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".