title: Lysosome associated membrane proteins maintain pancreatic acinar cell homeostasis: LAMP-2 deficient mice develop pancreatitis.
abstract: OBJECTIVE
  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 de-glycosylation 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 LAMPs' bulk de-glycosylation, but induces their degradation via CatB-mediated cleavage of 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, stimulates the basal and inhibits CCK-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.
authors.affiliation: VA Greater Los Angeles Healthcare System ; David Geffen School of Medicine, University of California at Los Angeles, CA.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Mareninova
authors.affiliation: Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University Greifswald, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Sendler
authors.affiliation: Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University Greifswald, Germany.
authors.forename: Sudarshan Ravi
authors.initials: SR
authors.lastname: Malla
authors.affiliation: David Geffen School of Medicine, University of California at Los Angeles, CA.
authors.forename: Iskandar
authors.initials: I
authors.lastname: Yakubov
authors.affiliation: Harbor-UCLA Medical Center, Torrance, CA.
authors.forename: Samuel W
authors.initials: SW
authors.lastname: French
authors.affiliation: VA Greater Los Angeles Healthcare System ; David Geffen School of Medicine, University of California at Los Angeles, CA.
authors.forename: Elmira
authors.initials: E
authors.lastname: Tokhtaeva
authors.affiliation: VA Greater Los Angeles Healthcare System ; David Geffen School of Medicine, University of California at Los Angeles, CA.
authors.forename: Olga
authors.initials: O
authors.lastname: Vagin
authors.affiliation: University Medical Center Utrecht, The Netherlands.
authors.forename: Viola
authors.initials: V
authors.lastname: Oorschot
authors.affiliation: Anatomical Institute, Christian-Albrechts-University Kiel, Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: Lüllmann-Rauch
authors.affiliation: Biochemical Institute, Christian-Albrechts-University Kiel, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Blanz
authors.affiliation: David Geffen School of Medicine, University of California at Los Angeles, CA.
authors.forename: David
authors.initials: D
authors.lastname: Dawson
authors.affiliation: University Medical Center Utrecht, The Netherlands.
authors.forename: Judith
authors.initials: J
authors.lastname: Klumperman
authors.affiliation: Harbor-UCLA Medical Center, Torrance, CA.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Lerch
authors.affiliation: Harbor-UCLA Medical Center, Torrance, CA.
authors.forename: Julia
authors.initials: J
authors.lastname: Mayerle
authors.affiliation: VA Greater Los Angeles Healthcare System ; David Geffen School of Medicine, University of California at Los Angeles, CA.
authors.forename: Ilya
authors.initials: I
authors.lastname: Gukovsky
authors.affiliation: VA Greater Los Angeles Healthcare System ; David Geffen School of Medicine, University of California at Los Angeles, CA.
authors.forename: Anna S
authors.initials: AS
authors.lastname: Gukovskaya
keywords: amylase secretion; autophagy; cathepsin B; cerulein