pXBP1(U), a Negative Regulator of the Unfolded Protein Response Activator pXBP1(S), Targets ATF6 but not ATF4 in Proteasome-mediated Degradation
Bibliographic record
Abstract
Cells from yeast to humans activate unconventional mRNA splicing when unfolded proteins accumulate in the endoplasmic reticulum (ER) under ER stress conditions. The substrate of this splicing in mammalian cells is XBP1 mRNA, which encodes the unfolded protein response (UPR)-specific transcription factor XBP1. The C-terminal region of XBP1 is switched as a result of the splicing. Thus, unspliced and spliced mRNAs produce pXBP1(U) of 261 aa and pXBP1(S) of 376 aa, respectively, with the N-terminal region containing the DNA-binding domain shared. As the pXBP1(S)-specific C-terminal region functions as an activation domain, pXBP1(S) can activate transcription efficiently. We recently found that pXBP1(U) shuttles between the nucleus and cytoplasm, owing to the presence of a nuclear exclusion signal in the pXBP1(U)-specific C-terminal region, in marked contrast to the exclusively nuclear localization of pXBP1(S). pXBP1(U) can associate with pXBP1(S), and pXBP1(U)-pXBP1(S) complex is rapidly degraded by the proteasome. Two other transcription factors are activated in response to ER stress, namely ATF6 and ATF4. ATF6 is a UPR-specific transcription factor, whereas ATF4 is activated by not only ER stress but also various other stimuli. In this study, we show that pXBP1(U) targets the active form of ATF6 but not ATF4 for destruction by the proteasome via direct association. This enhanced degradation is mediated by the degradation domain located at the pXBP1(U)-specific C-terminal end. We conclude that pXBP1(U) functions as a negative regulator of the UPR-specific transcription factors ATF6 and pXBP1(S).
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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) | 0.001 | 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) | 0.002 | 0.001 |
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".