Polycystin-2 is regulated by endoplasmic reticulum-associated degradation
Bibliographic record
Abstract
Endoplasmic reticulum(ER)-associated degradation (ERAD) is an essential process for cell homeostasis and remains not well understood. During ERAD, misfolded proteins are recognized, ubiquitinated on ER and subsequently retro-translocated/dislocated from ER to the 26S proteasome in the cytosol for proteolytic elimination. Polycystin-2 (PC2), a member of the transient receptor potential superfamily of cation channels, is a Ca channel mainly located on ER and primary cilium membranes of cells. Mutations in PC2 are associated with autosomal dominant polycystic kidney disease (ADPKD). The cellular and molecular mechanisms underlying the PC2-associated pathogenesis remain unclear. Here we show that PC2 degradation is regulated by the ERAD pathway through the ubiquitin-proteasome system. PC2 interacted with ATPase p97, a well-known ERAD component extracting substrates from ER, and immobilized it in perinuclear regions. PC2 also interacted with Herp, an ubiquitin-like protein implicated in regulation of ERAD. We found that Herp is required for and promotes PC2 degradation. ER stress accelerates the retro-translocation of PC2 for cytosolic degradation, at least in part through increasing the Herp expression. Thus, PC2 is a novel ERAD substrate. Herp also promoted, to varied degrees, the degradation of PC2 truncation mutants, including two pathogenic mutants R872X and E837X, as long as they interact with Herp. In contrast, Herp did not interact with, and has no effect on the degradation of, PC2 mutant missing both the N- and C-termini. The ERAD machinery may thus be important for ADPKD pathogenesis because the regulation of PC2 expression by the ERAD pathway is altered by mutations in PC2.
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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 | 0.000 | 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) | 0.000 | 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".