ADP-ribosylation factor 1 protein regulates trypsinogen activation via organellar trafficking of procathepsin B protein and autophagic maturation in acute pancreatitis.

The Journal of Biological Chemistry
Lidiya S OrlichenkoVijay P Singh

Abstract

Several studies have suggested that autophagy might play a deleterious role in acute pancreatitis via intra-acinar activation of digestive enzymes. The prototype for this phenomenon is cathepsin B-mediated trypsin generation. To determine the organellar basis of this process, we investigated the subcellular distribution of the cathepsin B precursor, procathepsin B. We found that procathepsin B is enriched in Golgi-containing microsomes, suggesting a role for the ADP-ribosylation (ARF)-dependent trafficking of cathepsin B. Indeed, caerulein treatment increased processing of procathepsin B, whereas a known ARF inhibitor brefeldin A (BFA) prevented this. Similar treatment did not affect processing of procathepsin L. BFA-mediated ARF1 inhibition resulted in reduced cathepsin B activity and consequently reduced trypsinogen activation. However, formation of light chain 3 (LC3-II) was not affected, suggesting that BFA did not prevent autophagy induction. Instead, sucrose density gradient centrifugation and electron microscopy showed that BFA arrested caerulein-induced autophagosomal maturation. Therefore, ARF1-dependent trafficking of procathepsin B and the maturation of autophagosomes results in cathepsin B-mediated trypsinogen activ...Continue Reading

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Citations

Dec 1, 2015·Cellular and Molecular Gastroenterology and Hepatology·Scott W MessengerGuy E Groblewski
Sep 6, 2014·The EMBO Journal·Karin B AckemaAnne Spang
Apr 21, 2020·American Journal of Physiology. Gastrointestinal and Liver Physiology·Xin YeGuoyong Hu
Aug 11, 2018·Scientific Reports·Sergiy KostenkoVijay P Singh
Sep 21, 2020·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Bin LiGuoyong Hu

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