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 diseases. The unfolded protein response (UPR) and autophagy may be activated to sustain proteostasis. In GECs during ER stress, the COPII vesicle component Sec23B localizes in autophagosomes along with collagen IV-α5 (COL4A5). Thus, the secretory pathway is redirected to ERphagy (ER-specific autophagy), with COL4A5 being a potential ERphagy substrate. In GECs, ERphagy was facilitated by the activation of the UPR transducer IRE1α. Discovery proteomics in GECs exposed to ER stress showed that IRE1α facilitated expression of Surf4, an ER-COPII vesicle cargo receptor. The present study examines whether Surf4 may redirect misfolded proteins for autophagosomal degradation. Methods: We studied IRE1α-replete (control) GECs in culture and GECs with genetic knockout (KO) of IRE1α. Immunofluorescence microscopy was used to quantify autophagosome number/area by setting a suitable particle size/threshold. Results: Basal Surf4 expression was greater in control compared to IRE1α KO GECs. During ER stress induced with tunicamycin (TM), there was activation of the UPR, although 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. TM increased COL4A5 particle area and colocalization of Surf4 with COL4A5 in control and KO GECs, implying that during ER stress, some of the COL4A5 localizes in autophagosomes. The GEC toxin adriamycin (ADR) induced autophagy (LC3-II), but not the UPR. Unlike TM, ADR did not promote localization of Surf4 or COL4A5 in autophagosomes. However, both TM and ADR could enhance colocalization of LC3-II and Hsp60 (a mitochondrial protein), consistent with mitophagy. Analysis of a human glomerular gene expression dataset showed increased Surf4 and UPR gene expression in membranous nephropathy and focal segmental glomerulosclerosis compared to healthy controls. Conclusion: During ER stress, 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 proteostasis. Funding: Private Foundation Support, 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".