TY - JOUR
T1 - Lysosome-Associated Membrane Proteins (LAMP) Maintain Pancreatic Acinar Cell Homeostasis
T2 - LAMP-2-Deficient Mice Develop Pancreatitis
AU - Mareninova, Olga A.
AU - Sendler, Matthias
AU - Malla, Sudarshan Ravi
AU - Yakubov, Iskandar
AU - French, Samuel W.
AU - Tokhtaeva, Elmira
AU - Vagin, Olga
AU - Oorschot, Viola
AU - Lüllmann-Rauch, Renate
AU - Blanz, Judith
AU - Dawson, David
AU - Klumperman, Judith
AU - Lerch, Markus M.
AU - Mayerle, Julia
AU - Gukovsky, Ilya
AU - Gukovskaya, Anna S.
N1 - Publisher Copyright:
© 2015 The Authors.
PY - 2015/11
Y1 - 2015/11
N2 - 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.
AB - 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.
KW - Amylase secretion
KW - Autophagy
KW - Cathepsin B
KW - Cerulein
UR - http://www.scopus.com/inward/record.url?scp=85014530641&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85014530641&partnerID=8YFLogxK
U2 - 10.1016/j.jcmgh.2015.07.006
DO - 10.1016/j.jcmgh.2015.07.006
M3 - Article
C2 - 26693174
AN - SCOPUS:85014530641
SN - 2352-345X
VL - 1
SP - 678
EP - 694
JO - CMGH
JF - CMGH
IS - 6
ER -