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<p>Acute pancreatitis is caused by a premature activation of digestive proteases. One hypothesis is based on the proteolytic activation of the serine protease trypsinogen by the lysosomal enzyme cathepsin B (CTSB) after co-localization in the same subcellular compartment. The ER-cargo receptor protein CLN8 (ceroid lipofuscinosis, neuronal) mediates cathepsin transport from the endoplasmic reticulum (ER), the site of enzyme synthesis, to the trans-Golgi system, from which they are distributed to their final destinations. The aim of this study is to investigate the role of CLN8 in acute pancreatitis and intracellular cathepsin trafficking by using isolated pancreatic acinar cells, a CLN8-deficient (<i>Cln8</i><sup><i>mnd</i></sup>/MsrJ) mouse model, and 266–6 mouse pancreatic acinar tumor cells in which the <i>Cln8</i> gene was inactivated by CRISPR/Cas9. Loss of CLN8 mitigated the early phase of acute pancreatitis but did not prevent it completely. We still observed CTSB expression in the endo-lysosomal and secretory compartment albeit enzyme activation was decreased. At later disease stages pancreatic injury increased along with an upregulation of ER-phagy shown by an overexpression of LC3B and the ER-phagy receptor FAM134B as well as autophagolysosome formation and increased ER stress. In summary, our data show that acute pancreatitis still occurs despite disruption of the EGRESS (ER-to-Golgi relaying of enzymes of the lysosomal system) complex implicating alternative intracellular enzyme delivery routes. They also illustrate that ER-stress and ER-phagy aggravate severity at later course of pancreatitis.</p>

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Loss of the ER-cargo protein CLN8 increases severity of acute pancreatitis and upregulates ER-stress and ER-phagy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月15日

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  • Lukas Zierke,
  • Marcel Gischke,
  • Matthias Sendler,
  • Frank Ulrich Weiss,
  • Silvia Ribback,
  • Dariush Skowronek,
  • Matthias Rath,
  • Henry Völzke,
  • Markus M. Lerch,
  • Ali A. Aghdassi

摘要

Acute pancreatitis is caused by a premature activation of digestive proteases. One hypothesis is based on the proteolytic activation of the serine protease trypsinogen by the lysosomal enzyme cathepsin B (CTSB) after co-localization in the same subcellular compartment. The ER-cargo receptor protein CLN8 (ceroid lipofuscinosis, neuronal) mediates cathepsin transport from the endoplasmic reticulum (ER), the site of enzyme synthesis, to the trans-Golgi system, from which they are distributed to their final destinations. The aim of this study is to investigate the role of CLN8 in acute pancreatitis and intracellular cathepsin trafficking by using isolated pancreatic acinar cells, a CLN8-deficient (Cln8mnd/MsrJ) mouse model, and 266–6 mouse pancreatic acinar tumor cells in which the Cln8 gene was inactivated by CRISPR/Cas9. Loss of CLN8 mitigated the early phase of acute pancreatitis but did not prevent it completely. We still observed CTSB expression in the endo-lysosomal and secretory compartment albeit enzyme activation was decreased. At later disease stages pancreatic injury increased along with an upregulation of ER-phagy shown by an overexpression of LC3B and the ER-phagy receptor FAM134B as well as autophagolysosome formation and increased ER stress. In summary, our data show that acute pancreatitis still occurs despite disruption of the EGRESS (ER-to-Golgi relaying of enzymes of the lysosomal system) complex implicating alternative intracellular enzyme delivery routes. They also illustrate that ER-stress and ER-phagy aggravate severity at later course of pancreatitis.