Cathepsin B hyperactivation facilitates exosome release of CVB3 particles and exacerbation of acute pancreatitis by impairing lysosomal integrity and acidification
Bibliographic record
Abstract
Lysosomal cathepsin B (CTSB) exhibits diverse roles in physiological and pathological processes. Upregulation and trypsinogen-activating function of CTSB have been reported in experimental secretagogue-elicited AP. Whether CTSB regulates the lysosome pathway and viral release in viral acute pancreatitis (AP) remains obscure. In a murine model of Coxsackievirus 3 (CVB3)-induced AP, we tested effects of CTSB on lysosome integrity and exosome secretion. CVB3 infection does- and time-dependently upregulates expression and activity of CTSB, the most elevated CTS in pancreas, and induces lysosomal instability and extra-lysosomal translocation of CTSB. Overexpression of CTSB increases viral replication. Inhibition of CTSB with CA074Me reduces virion release via rescuing lysosome integrity and acidity. Mechanically, CTSB hyperactivation and inappropriate cytoplasmic translocation increase viral infections by decreasing LAMP-1 + lysosomes, exacerbating lysosomal membrane permeabilization (LMP), and enhancing exosomal release of virions. Pharmaceutical inhibition of CTSB improves AP pathology via reducing viral infection. Our study reveals a critical role of hyperactivated CTSB in disrupting lysosome integrity, facilitating exosomal release of CVB3 particles and exacerbation of pancreas pathology in AP. These findings offer new insights into the pathogenesis of viral AP and suggest that CTSB and exosome are potential therapeutic targets for viral AP. IMPORTANCE: This study uncovers a critical role of lysosome cathepsin B (CTSB) in exacerbating viral acute pancreatitis (AP). CVB3 infection of acinar cells induces lysosomal membrane permeability and CTSB cytosolic translocation. Hyperactivated CTSB increases viral infections by decreasing lysosomes, exacerbating LMP, and enhancing exosomal release of virions. Pharmaceutical inhibition of CTSB protects mice against viral dissemination and AP pathology, suggesting that CTSB and exosome are potential therapeutic targets for viral AP.
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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".