ZNF33B facilitates Japanese encephalitis virus replication by controlling HSPB1/8-mediated SUMOylation of nonstructural protein 5
Bibliographic record
Abstract
Japanese encephalitis virus (JEV) is a significant flavivirus that poses a threat to public health, as it induces encephalitis in humans and reproductive disorders in sows. We have recently identified that zinc finger protein 33B (ZNF33B) is required for JEV infection by CRISPR-based functional genomic screening, yet the precise functions and mechanisms are not fully comprehended. In this study, ZNF33B was found to be involved in JEV infection, wherein it bound with JEV RNA to enhance its stability during replication. Additionally, ZNF33B underwent translocation from the nucleus to the cytoplasm to associate with viral replication complexes during JEV infection. Furthermore, ZNF33B stabilized JEV nonstructural protein 5 (NS5), rather than NS3, by inhibiting its polyubiquitination and promoting SUMOylation. The SUMOylation of JEV NS5 was found to compete with its ubiquitination at lysine residues 269 and 846. Through immunoprecipitation-mass spectrometry, we identified heat shock proteins HSPB1 and HSPB8 as potential mediators of the SUMOylation of JEV NS5. ZNF33B was shown to recruit HSPB1/8 to facilitate NS5 SUMOylation. Overall, our study highlighted the importance of ZNF33B in facilitating the SUMOylation of JEV NS5 through the recruitment of HSPB1 and HSPB8.IMPORTANCEJapanese encephalitis virus (JEV) poses a severe global health threat, yet host factors regulating its replication remain poorly understood. Our study identifies ZNF33B as a critical host protein that enhances JEV replication by stabilizing viral RNA and facilitating SUMOylation of the viral polymerase NS5. We demonstrate that ZNF33B recruits HSPB1/8 as SUMO E3 ligases to modify NS5, thereby counteracting its polyubiquitination and proteasomal degradation. This SUMOylation-ubiquitination crosstalk at lysine residues 269 and 846 ensures NS5 stability, essential for viral replication. These findings unveil a novel mechanism by which JEV exploits host post-translational machinery to sustain replication. Targeting ZNF33B or viral SUMOylation could offer therapeutic strategies against JEV and related flaviviruses, with great significance for the development of antiviral interventions.
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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".