Peripheral Endoplasmic Reticulum Localization of Gp78 Ubiquitin Ligase Activity
Bibliographic record
Abstract
Gp78 (also known as AMFR and RNF45) is an E3 ubiquitin ligase that targets proteins for proteasomal degradation through endoplasmic reticulum (ER)-associated degradation (ERAD). In this study, we showed that gp78-mediated ubiquitylation is initiated in the peripheral ER. Substrate monoubiquitylation and gp78 CUE domain integrity restricted substrate to the peripheral ER, where CUE domain interactions and polyubiquitylation reduced gp78 mobility. Derlin-1 and derlin-2, which are involved in the retrotranslocation of ERAD substrates, localized to a central, juxtanuclear ER domain, where polyubiquitylated proteins accumulated upon proteasome inhibition. Transfer of polyubiquitylated substrate to the central ER was dependent on ubiquitin chain elongation and recruitment of the AAA ATPase p97 (also known as VCP). HT-1080 fibrosarcoma cells expressed elevated levels of endogenous gp78, which was associated with segregation of ubiquitylated substrate to the peripheral ER and its polyubiquitin-dependent redistribution to the central ER upon proteasome inhibition. Therefore, the peripheral ER is the site of gp78 ubiquitin ligase activity. Delivery of ubiquitylated substrate to the central ER was regulated by ubiquitin chain elongation and opposing actions of gp78 CUE domain interactions and p97 recruitment.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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) | 0.000 | 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 teacher head, 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".