Herpes Simplex Virus 1 UL41 Protein Suppresses the IRE1/XBP1 Signal Pathway of the Unfolded Protein Response via Its RNase Activity
Bibliographic record
Abstract
During viral infection, accumulation of viral proteins can cause stress in the endoplasmic reticulum (ER) and trigger the unfolded protein response (UPR) to restore ER homeostasis. The inositol-requiring enzyme 1 (IRE1)-dependent pathway is the most conserved of the three UPR signal pathways. Upon activation, IRE1 splices out an intron from the unspliced inactive form of X box binding protein 1 [XBP1(u)] mRNA and produces a transcriptionally potent spliced form [XBP1(s)]. Previous studies have reported that the IRE1/XBP1 pathway is inhibited upon herpes simplex virus 1 (HSV-1) infection; however, the underlying molecular mechanism is still elusive. Here, we uncovered a role of the HSV-1 UL41 protein in inhibiting the IRE1/XBP1 signal pathway. Ectopic expression of UL41 decreased the expression of XBP1 and blocked XBP1 splicing activation induced by the ER stress inducer thapsigargin. Wild-type (WT) HSV-1, but not the UL41-null mutant HSV-1 (R2621), decreased XBP1 mRNA induced by thapsigargin. Nevertheless, infection with both WT HSV-1 and R2621 without drug pretreatment could reduce the mRNA and protein levels of XBP1(s), and additional mechanisms might contribute to this inhibition of XBP1(s) during R2621 infection. Taking these findings together, our results reveal XBP1 as a novel target of UL41 and provide insights into the mechanism by which HSV-1 modulates the IRE1/XBP1 pathway. IMPORTANCE: During viral infection, viruses hijack the host translation apparatus to produce large amounts of viral proteins, which leads to ER stress. To restore ER homeostasis, cells initiate the UPR to alleviate the effects of ER stress. The IRE1/XBP1 pathway is the most conserved UPR branch, and it activates ER-associated protein degradation (ERAD) to reduce the ER load. The IRE1/XBP1 branch is repressed during HSV-1 infection, but little is known about the underlying molecular mechanism. Our results show for the first time that UL41 suppresses the IRE1/XBP1 signal pathway by reducing the accumulation of XBP1 mRNA, and characterization of the underlying molecular mechanism provides new insight into the modulation of UPR by HSV-1.
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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 | 0.001 |
| 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".