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

Lidiya Orlichenko, Donna B. Stolz, Pawan Noel, Jaideep Behari, Shiguang Liu, Vijay Prem Singh

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 activation induced by caerulein.

Original languageEnglish (US)
Pages (from-to)24284-24293
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number29
DOIs
StatePublished - Jul 13 2012

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ADP-Ribosylation Factor 1
Trypsinogen
Brefeldin A
Cathepsin B
Pancreatitis
Ceruletide
Chemical activation
Autophagy
Proteins
Enzyme Activation
Density Gradient Centrifugation
Centrifugation
Processing
Microsomes
Adenosine Diphosphate
Trypsin
Electron microscopy
Sucrose
Electron Microscopy
procathepsin B

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

ADP-ribosylation factor 1 protein regulates trypsinogen activation via organellar trafficking of procathepsin B protein and autophagic maturation in acute pancreatitis. / Orlichenko, Lidiya; Stolz, Donna B.; Noel, Pawan; Behari, Jaideep; Liu, Shiguang; Singh, Vijay Prem.

In: Journal of Biological Chemistry, Vol. 287, No. 29, 13.07.2012, p. 24284-24293.

Research output: Contribution to journalArticle

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