A Noncanonical Role for IRE1α in Podocyte Endoplasmic Reticulum (ER)-Phagy
Bibliographic record
Abstract
Background: Glomerular diseases involving podocyte (glomerular epithelial cell; GEC) injury feature endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). Inositol requiring enzyme-1α (IRE1α), a UPR transducer, mediates chaperone production and autophagy in podocytes during ER stress. Selective autophagy of the ER (ERphagy) is dependent on ER-resident adaptors (e.g. RTN3L) and is stimulated by ER stress. ER-derived coat protein complex II (COPII) vesicles may participate in the delivery of ER cargo to autophagosomes; however, regulation and importance of ERphagy in glomerular disease are not understood. Methods: We employed mice with podocyte-specific deletion of IRE1α and littermate controls. IRE1α knockout (KO) and control GECs were produced from these mice. GECs were incubated with tunicamycin (TM) to induce ER stress. Results: Mass spectrometry analysis of TM-stimulated control and IRE1α KO GECs showed that in addition to ER chaperones, proteins in the secretory pathway, including the COPII component Sec23B, were increased in an IRE1α-dependent manner. By immunoblotting, TM enhanced Sec23B and RTN3L expression in control, but not IRE1α KO GECs. By immunofluorescence microscopy, in control GECs, TM increased the biogenesis of LC3 and Sec23B particles, as well as colocalization of Sec23B with LC3 and RTN3L with LC3; increases were attenuated in IRE1α KO GECs. Thus, deletion of IRE1α impaired delivery of COPII vesicles and RTN3L-coated ER fragments to autophagosomes. Knockdown of Sec23B with siRNAs reduced autophagosome formation in TM-treated control GECs. After blocking protein synthesis with cycloheximide, TM stimulated degradation of RTN3L in control GECs, consistent with ERphagy flux, but RTN3L degradation was impaired in IRE1α KO cells. Similarly, TM induced degradation of α3,4,5 collagen IV in control, but not IRE1α KO GECs, suggesting that collagen IV is an IRE1α-dependent ERphagy substrate. In adriamycin nephrosis, where IRE1α activates an adaptive UPR and autophagy, expression of Sec23B and RTN3L was increased in glomeruli of control, but not IRE1α KO mice. Conclusions: During ER stress, IRE1α redirects a subset of Sec23B-positive COPII vesicles to deliver RTN3L-coated ER fragments to autophagosomes. ERphagy is a novel outcome of the IRE1α pathway in podocytes and may play a cytoprotective role in glomerular diseases. 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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".