Role of Cargo Receptor Surf4 in Podocyte Proteostasis
Bibliographic record
Abstract
Background: Protein misfolding in the endoplasmic reticulum (ER) of podocytes/glomerular epithelial cells (GECs) induces ER stress and contributes to the pathogenesis of glomerular disease. Activation of the unfolded protein response (UPR) and autophagy sustains proteostasis. In GECs during ER stress, the secretory pathway may be redirected to ERphagy (ER-specific autophagy), with collagen IV-α5 (COL4A5) being a potential ERphagy substrate. ERphagy was enhanced by the UPR transducer IRE1α. Discovery proteomics in GECs exposed to ER stress showed that IRE1α facilitated expression of Surf4, an ER cargo receptor. The present study examines whether Surf4 redirects misfolded proteins for autophagosomal degradation. Methods: We studied cultured GECs and mice with genetic knockout (KO) of IRE1α in podocytes. Autophagosome number/area in GECs was quantified by immunofluorescence microscopy, setting a suitable autophagosome particle size and threshold. Results: Basal Surf4 expression was greater in control compared to IRE1α KO GECs. Tunicamycin (TM) activated the UPR, but Surf4 did not increase above basal levels. TM increased LC3-II and Surf4 particle areas, as well as colocalization of LC3 and Surf4; increases were smaller in KO GECs compared to control. Thus, during ER stress, a subset of Surf4 localizes in autophagosomes. In GECs, TM increased COL4A5-wild type (WT) particle area and colocalization of Surf4 with COL4A5-WT, implying that during ER stress, a subset of COL4A5 localizes in autophagosomes. Compared to COL4A5-WT, the human COL4A5-C1567R mutant (which is misfolded) showed enhanced basal colocalization with Surf4 and with LC3-II; colocalization was similar to COL4A5-WT after TM treatment. Degradation of COL4A5-C1567R was more rapid compared to COL4A5-WT and was comparable to COL4A5-WT degradation in the presence of TM. Glomerular Surf4 expression was greater in control mice with adriamycin nephrosis compared to IRE1α KO mice and untreated mice. Analysis of a human glomerular gene expression dataset showed greater Surf4 and UPR gene expression in membranous nephropathy and focal segmental glomerulosclerosis compared to healthy controls. Conclusion: During ER stress, a subset of Surf4 is redirected from the secretory pathway to autophagosomes. Surf4 may help deliver misfolded ER cargo such as COL4A5 for degradation. This represents a novel role for Surf4 in sustaining podocyte proteostasis. Funding: Government Support – Non-U.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) | 0.000 | 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) | 0.002 | 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".