The molecular basis of integrated stress response silencing
Bibliographic record
Abstract
Abstract Chronic stress response activation impairs cell survival and causes devastating degenerative diseases. To counteract this, cells deploy dedicated silencing factors, such as the E3 ligase SIFI that terminates the mitochondrial stress response. How a single enzyme can sense stress across cells and elicit timely stress response inactivation is poorly understood. Here, we report the structure of human SIFI, which revealed how this 1.3MDa complex can target hundreds of proteins for accurate stress response silencing. SIFI attaches the first ubiquitin to substrates using flexible domains within an easily accessible scaffold, yet builds linkage-specific ubiquitin chains at distinct, sterically restricted elongation modules in its periphery. Ubiquitin handover via a ubiquitin-like domain couples versatile substrate modification to precise chain elongation. Stress response silencing therefore exploits a catalytic mechanism that is geared to process many diverse proteins and hence allows a single enzyme to monitor and, if appropriate, modulate a complex cellular state.
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".