Targeting and inactivation of endoplasmic reticulum chaperones by L‐homocysteine: a pathway to ER stress
Bibliographic record
Abstract
Homocysteine may disrupt protein folding within the endoplasmic reticulum (ER) causing ER stress and activating the unfolded protein response. We hypothesize that L‐homocysteine induces ER stress by interacting with and modulating the activity of 78‐kDa glucose‐regulated protein (GRP78) and protein disulfide isomerase (PDI). In vitro S ‐homocysteinylation of human recombinant GRP78 (hrGRP78) and rat recombinant PDI (rrPDI) was identified by SDS‐PAGE and phosphorimage analysis. We determined that 0.27 mol of 35 S ‐L‐homocysteine and 0.38 mol of 35 S ‐L‐homocysteine react per mol of hrGRP78 and rrPDI, respectively. Evidence for in situ S ‐homocysteinylation of GRP78 and PDI was obtained by incubating rat liver microsomes with 35 S ‐L‐homocysteine, immunoprecipitating with mouse anti‐KDEL monoclonal antibodies, phosphorimaging and LC/MS/MS. Using surface plasmon resonance, we observed weaker interactions between peptide pp38 and S ‐homocysteinylated‐hrGRP78, compared to native hrGRP78 protein. In contrast, L‐homocysteine stimulated the activity of PDI in the insulin precipitation assay. We conclude that L‐homocysteine directly targets and alters the function of the ER resident chaperones GRP78 and PDI. This pathway links homocysteine to ER stress, cardiovascular disease and other disorders associated with abnormal protein accumulation. (Supported by NIH, HL52234 (DWJ)).
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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 | 0.000 |
| 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".