Lysosome-Associated Membrane Proteins (LAMP) Maintain Pancreatic Acinar Cell Homeostasis: LAMP-2âDeficient Mice Develop PancreatitisSummary
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...
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Format: | Article |
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Elsevier
2015-11-01
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Series: | Cellular and Molecular Gastroenterology and Hepatology |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X15001290 |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Lysosome-Associated Membrane Proteins (LAMP) Maintain Pancreatic Acinar Cell Homeostasis: LAMP-2âDeficient Mice Develop PancreatitisSummary Cellular and Molecular Gastroenterology and Hepatology |
author_facet |
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 |
author_sort |
Olga A. Mareninova |
title |
Lysosome-Associated Membrane Proteins (LAMP) Maintain Pancreatic Acinar Cell Homeostasis: LAMP-2âDeficient Mice Develop PancreatitisSummary |
title_short |
Lysosome-Associated Membrane Proteins (LAMP) Maintain Pancreatic Acinar Cell Homeostasis: LAMP-2âDeficient Mice Develop PancreatitisSummary |
title_full |
Lysosome-Associated Membrane Proteins (LAMP) Maintain Pancreatic Acinar Cell Homeostasis: LAMP-2âDeficient Mice Develop PancreatitisSummary |
title_fullStr |
Lysosome-Associated Membrane Proteins (LAMP) Maintain Pancreatic Acinar Cell Homeostasis: LAMP-2âDeficient Mice Develop PancreatitisSummary |
title_full_unstemmed |
Lysosome-Associated Membrane Proteins (LAMP) Maintain Pancreatic Acinar Cell Homeostasis: LAMP-2âDeficient Mice Develop PancreatitisSummary |
title_sort |
lysosome-associated membrane proteins (lamp) maintain pancreatic acinar cell homeostasis: lamp-2âdeficient mice develop pancreatitissummary |
publisher |
Elsevier |
series |
Cellular and Molecular Gastroenterology and Hepatology |
issn |
2352-345X |
publishDate |
2015-11-01 |
description |
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 |
url |
http://www.sciencedirect.com/science/article/pii/S2352345X15001290 |
work_keys_str_mv |
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doaj-cb4a33f8eeb6420680ed96b3e0cadf952020-11-24T23:02:41ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2015-11-0116678694Lysosome-Associated Membrane Proteins (LAMP) Maintain Pancreatic Acinar Cell Homeostasis: LAMP-2âDeficient Mice Develop PancreatitisSummaryOlga A. Mareninova0Matthias Sendler1Sudarshan Ravi Malla2Iskandar Yakubov3Samuel W. French4Elmira Tokhtaeva5Olga Vagin6Viola Oorschot7Renate Lüllmann-Rauch8Judith Blanz9David Dawson10Judith Klumperman11Markus M. Lerch12Julia Mayerle13Ilya Gukovsky14Anna S. Gukovskaya15VA Greater Los Angeles Healthcare System, Los Angeles, California; David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CaliforniaDepartment of Medicine A, University Medicine, Ernst-Moritz-Arndt University Greifswald, Greifswald, GermanyDepartment of Medicine A, University Medicine, Ernst-Moritz-Arndt University Greifswald, Greifswald, GermanyDavid Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CaliforniaHarbor-UCLA Medical Center, Torrance, CAVA Greater Los Angeles Healthcare System, Los Angeles, California; David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CaliforniaVA Greater Los Angeles Healthcare System, Los Angeles, California; David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CaliforniaUniversity Medical Center Utrecht, Utrecht, the Netherlands; Monash Micro Imaging, Monash University, Melbourne, Victoria, AustraliaAnatomical Institute, Christian-Albrechts-University Kiel, Kiel, GermanyBiochemical Institute, Christian-Albrechts-University Kiel, Kiel, GermanyDavid Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CaliforniaUniversity Medical Center Utrecht, Utrecht, the NetherlandsDepartment of Medicine A, University Medicine, Ernst-Moritz-Arndt University Greifswald, Greifswald, GermanyDepartment of Medicine A, University Medicine, Ernst-Moritz-Arndt University Greifswald, Greifswald, GermanyVA Greater Los Angeles Healthcare System, Los Angeles, California; David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CaliforniaVA Greater Los Angeles Healthcare System, Los Angeles, California; David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California; Correspondence Address correspondence to: Anna S. Gukovskaya, PhD, Pancreatic Research Group, West Los Angeles VA Healthcare Center, 11301 Wilshire Boulevard, Building 258, Room 340, Los Angeles, California 90073. fax: 310-268-4981.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, Ceruleinhttp://www.sciencedirect.com/science/article/pii/S2352345X15001290 |