1. Lysosome-Associated Membrane Proteins (LAMP) Maintain Pancreatic Acinar Cell Homeostasis: LAMP-2–Deficient Mice Develop Pancreatitis
- Author
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Renate Lüllmann-Rauch, Judith Blanz, Julia Mayerle, Ilya Gukovsky, Samuel W. French, Olga Vagin, Sudarshan R. Malla, Elmira Tokhtaeva, Iskandar Yakubov, Markus M. Lerch, Viola Oorschot, Matthias Sendler, Olga A. Mareninova, David W. Dawson, Judith Klumperman, and Anna S. Gukovskaya
- Subjects
Pathology ,genetic structures ,cathepsin B ,CCK, cholecystokinin ,MPO, myeloperoxidase ,cerulein ,Cat, cathepsin ,Cathepsin B ,0302 clinical medicine ,Trypsinogen activation ,Original Research ,LIMP-2, lysosomal integral membrane protein type-2 ,0303 health sciences ,Gastroenterology ,3. Good health ,Cell biology ,LAMP, lysosome-associated membrane proteins ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,IKKα, inhibitor of κB kinase α ,Pancreas ,autophagy ,medicine.medical_specialty ,PBS, phosphate-buffered saline ,Amylase Secretion ,rLAMP-1, recombinant mouse LAMP-1 ,Biology ,Cerulein ,LC3-II, microtubule-associated protein-1 light chain 3 ,α-SMA, α-smooth muscle actin ,03 medical and health sciences ,amylase secretion ,Genetic model ,Autophagy ,medicine ,Acinar cell ,Secretion ,CDE, choline-deficient, ethionine-supplemented diet ,lcsh:RC799-869 ,Arg, l-arginine ,030304 developmental biology ,EM, electron microscopy ,Hepatology ,IP, intraperitoneal(ly) ,medicine.disease ,eye diseases ,MS, mass spectrometry ,Pancreatitis ,lcsh:Diseases of the digestive system. Gastroenterology ,sense organs ,CR, cerulein ,PFA, paraformaldehyde - 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 LAMPsâ 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. Keywords: Amylase Secretion, Autophagy, Cathepsin B, Cerulein
- Published
- 2015
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