Lysosome-Associated Membrane Proteins (LAMP) Maintain Pancreatic Acinar Cell Homeostasis: LAMP-2-Deficient Mice Develop Pancreatitis

Olga A. Mareninova, Matthias Sendler, Sudarshan Ravi Malla, Iskandar Yakubov, Samuel W. French, Elmira Tokhtaeva, Olga Vagin, Viola Oorschot, Renate Lüllmann-Rauch, Judith Blanz, David Dawson, Judith Klumperman, Markus M. Lerch, Julia Mayerle, Ilya Gukovsky, Anna S. Gukovskaya*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

Background & Aims: The pathogenic mechanism of pancreatitis is poorly understood. Recent evidence implicates defective autophagy in pancreatitis responses; however, the pathways mediating impaired autophagy in pancreas remain largely unknown. Here, we investigate the role of lysosome associated membrane proteins (LAMPs) in pancreatitis. Methods: We analyzed changes in LAMPs in experimental models and human pancreatitis, and the underlying mechanisms: LAMP deglycosylation and degradation. LAMP cleavage by cathepsin B (CatB) was analyzed by mass spectrometry. We used mice deficient in LAMP-2 to assess its role in pancreatitis. Results: Pancreatic levels of LAMP-1 and LAMP-2 greatly decrease across various pancreatitis models and in human disease. Pancreatitis does not trigger the LAMPs' bulk deglycosylation but induces their degradation via CatB-mediated cleavage of the LAMP molecule close to the boundary between luminal and transmembrane domains. LAMP-2 null mice spontaneously develop pancreatitis that begins with acinar cell vacuolization due to impaired autophagic flux, and progresses to severe pancreas damage characterized by trypsinogen activation, macrophage-driven inflammation, and acinar cell death. LAMP-2 deficiency causes a decrease in pancreatic digestive enzymes content, and stimulates the basal and inhibits cholecystokinin-induced amylase secretion by acinar cells. The effects of LAMP-2 knockout and acute cerulein pancreatitis overlap, which corroborates the pathogenic role of LAMP decrease in experimental pancreatitis models. Conclusions: The results indicate a critical role for LAMPs, particularly LAMP-2, in maintaining pancreatic acinar cell homeostasis and provide evidence that defective lysosomal function, resulting in impaired autophagy, leads to pancreatitis. Mice with LAMP-2 deficiency present a novel genetic model of human pancreatitis caused by lysosomal/autophagic dysfunction.

Original languageEnglish (US)
Pages (from-to)678-694
Number of pages17
JournalCMGH
Volume1
Issue number6
DOIs
StatePublished - Nov 2015

Keywords

  • Amylase secretion
  • Autophagy
  • Cathepsin B
  • Cerulein

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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