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Impaired TFEB-mediated lysosomal biogenesis promotes the development of pancreatitis in mice and is associated with human pancreatitis.
Autophagy. 2019 11; 15(11):1954-1969.A

Abstract

Impaired macroautophagy/autophagy has been implicated in experimental and human pancreatitis. However, the transcriptional control governing the autophagy-lysosomal process in pancreatitis is largely unknown. We investigated the role and mechanisms of TFEB (transcription factor EB), a master regulator of lysosomal biogenesis, in the pathogenesis of experimental pancreatitis. We analyzed autophagic flux, TFEB nuclear translocation, lysosomal biogenesis, inflammation and fibrosis in GFP-LC3 transgenic mice, acinar cell-specific tfeb knockout (KO) and tfeb and tfe3 double-knockout (DKO) mice as well as human pancreatitis samples. We found that cerulein activated MTOR (mechanistic target of rapamycin kinase) and increased the levels of phosphorylated TFEB as well as pancreatic proteasome activities that led to rapid TFEB degradation. As a result, cerulein decreased the number of lysosomes resulting in insufficient autophagy in mouse pancreas. Pharmacological inhibition of MTOR or proteasome partially rescued cerulein-induced TFEB degradation and pancreatic damage. Furthermore, genetic deletion of tfeb specifically in mouse pancreatic acinar cells increased pancreatic edema, necrotic cell death, infiltration of inflammatory cells and fibrosis in pancreas after cerulein treatment. tfeb and tfe3 DKO mice also developed spontaneous pancreatitis with increased pancreatic trypsin activities, edema and infiltration of inflammatory cells. Finally, decreased TFEB nuclear staining was associated with human pancreatitis. In conclusion, our results indicate a critical role of impaired TFEB-mediated lysosomal biogenesis in promoting the pathogenesis of pancreatitis. Abbreviations: AC: acinar cell; AMY: amylase; ATP6V1A: ATPase, H+ transporting, lysosomal V1 subunit A; ATP6V1B2: ATPase, H+ transporting, lysosomal V1 subunit B2; ATP6V1D: ATPase, H+ transporting, lysosomal V1 subunit D; ATP6V1H: ATPase, H+ transporting, lysosomal V1 subunit H; AV: autophagic vacuole; CDE: choline-deficient, ethionine-supplemented; CLEAR: coordinated lysosomal expression and regulation; CQ: chloroquine; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; EM: electron microscopy; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; H & E: hematoxylin and eosin; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK1/ERK2: mitogen-activated protein kinase 1; MTORC1: mechanistic target of rapamycin kinase complex 1; ND: normal donor; NEU: neutrophil; PPARGC1A/PGC1α: peroxisome proliferator-activated receptor, gamma, coactivator 1 alpha; RIPA: radio-immunoprecipitation; RPS6: ribosomal protein S6; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TM: tamoxifen; WT: wild-type; ZG: zymogen granule.

Authors+Show Affiliations

Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center , Kansas City , USA.Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center , Kansas City , USA.Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center , Kansas City , USA.Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center , Kansas City , USA. Department of Toxicology, School of Public Health, Anhui Medical University , Hefei , China.Liver Center, University of Kansa Medical Center , Kansas City , USA.Department of Surgery, University of Kansa Medical Center , Kansas City , USA.Department of Surgery, University of Kansa Medical Center , Kansas City , USA.Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles , Los Angeles , CA , USA.Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles , Los Angeles , CA , USA.Department of Anatomy and Cell Biology, University of Kansas Medical Center , Kansas City , KS , USA.Telethon Institute of Genetics and Medicine, TIGEM , Pozzuoli , Italy. Medical Genetics, Department of Translational Medicine, Federico II University , Naples , Italy. Department of Molecular and Human Genetics, Baylor College of Medicine , Houston , TX , USA. Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital , Houston , TX , USA.Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health , Bethesda , MD , USA.Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center , Kansas City , USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

30894069

Citation

Wang, Shaogui, et al. "Impaired TFEB-mediated Lysosomal Biogenesis Promotes the Development of Pancreatitis in Mice and Is Associated With Human Pancreatitis." Autophagy, vol. 15, no. 11, 2019, pp. 1954-1969.
Wang S, Ni HM, Chao X, et al. Impaired TFEB-mediated lysosomal biogenesis promotes the development of pancreatitis in mice and is associated with human pancreatitis. Autophagy. 2019;15(11):1954-1969.
Wang, S., Ni, H. M., Chao, X., Wang, H., Bridges, B., Kumer, S., Schmitt, T., Mareninova, O., Gukovskaya, A., De Lisle, R. C., Ballabio, A., Pacher, P., & Ding, W. X. (2019). Impaired TFEB-mediated lysosomal biogenesis promotes the development of pancreatitis in mice and is associated with human pancreatitis. Autophagy, 15(11), 1954-1969. https://doi.org/10.1080/15548627.2019.1596486
Wang S, et al. Impaired TFEB-mediated Lysosomal Biogenesis Promotes the Development of Pancreatitis in Mice and Is Associated With Human Pancreatitis. Autophagy. 2019;15(11):1954-1969. PubMed PMID: 30894069.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Impaired TFEB-mediated lysosomal biogenesis promotes the development of pancreatitis in mice and is associated with human pancreatitis. AU - Wang,Shaogui, AU - Ni,Hong-Min, AU - Chao,Xiaojuan, AU - Wang,Hua, AU - Bridges,Brian, AU - Kumer,Sean, AU - Schmitt,Timothy, AU - Mareninova,Olga, AU - Gukovskaya,Anna, AU - De Lisle,Robert C, AU - Ballabio,Andrea, AU - Pacher,Pal, AU - Ding,Wen-Xing, Y1 - 2019/03/30/ PY - 2019/3/22/pubmed PY - 2020/8/6/medline PY - 2019/3/22/entrez KW - Autophagy KW - cerulein KW - experimental pancreatitis KW - lysosome KW - transcription factor SP - 1954 EP - 1969 JF - Autophagy JO - Autophagy VL - 15 IS - 11 N2 - Impaired macroautophagy/autophagy has been implicated in experimental and human pancreatitis. However, the transcriptional control governing the autophagy-lysosomal process in pancreatitis is largely unknown. We investigated the role and mechanisms of TFEB (transcription factor EB), a master regulator of lysosomal biogenesis, in the pathogenesis of experimental pancreatitis. We analyzed autophagic flux, TFEB nuclear translocation, lysosomal biogenesis, inflammation and fibrosis in GFP-LC3 transgenic mice, acinar cell-specific tfeb knockout (KO) and tfeb and tfe3 double-knockout (DKO) mice as well as human pancreatitis samples. We found that cerulein activated MTOR (mechanistic target of rapamycin kinase) and increased the levels of phosphorylated TFEB as well as pancreatic proteasome activities that led to rapid TFEB degradation. As a result, cerulein decreased the number of lysosomes resulting in insufficient autophagy in mouse pancreas. Pharmacological inhibition of MTOR or proteasome partially rescued cerulein-induced TFEB degradation and pancreatic damage. Furthermore, genetic deletion of tfeb specifically in mouse pancreatic acinar cells increased pancreatic edema, necrotic cell death, infiltration of inflammatory cells and fibrosis in pancreas after cerulein treatment. tfeb and tfe3 DKO mice also developed spontaneous pancreatitis with increased pancreatic trypsin activities, edema and infiltration of inflammatory cells. Finally, decreased TFEB nuclear staining was associated with human pancreatitis. In conclusion, our results indicate a critical role of impaired TFEB-mediated lysosomal biogenesis in promoting the pathogenesis of pancreatitis. Abbreviations: AC: acinar cell; AMY: amylase; ATP6V1A: ATPase, H+ transporting, lysosomal V1 subunit A; ATP6V1B2: ATPase, H+ transporting, lysosomal V1 subunit B2; ATP6V1D: ATPase, H+ transporting, lysosomal V1 subunit D; ATP6V1H: ATPase, H+ transporting, lysosomal V1 subunit H; AV: autophagic vacuole; CDE: choline-deficient, ethionine-supplemented; CLEAR: coordinated lysosomal expression and regulation; CQ: chloroquine; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; EM: electron microscopy; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; H & E: hematoxylin and eosin; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK1/ERK2: mitogen-activated protein kinase 1; MTORC1: mechanistic target of rapamycin kinase complex 1; ND: normal donor; NEU: neutrophil; PPARGC1A/PGC1α: peroxisome proliferator-activated receptor, gamma, coactivator 1 alpha; RIPA: radio-immunoprecipitation; RPS6: ribosomal protein S6; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TM: tamoxifen; WT: wild-type; ZG: zymogen granule. SN - 1554-8635 UR - https://www.unboundmedicine.com/medline/citation/30894069/Impaired_TFEB_mediated_lysosomal_biogenesis_promotes_the_development_of_pancreatitis_in_mice_and_is_associated_with_human_pancreatitis_ DB - PRIME DP - Unbound Medicine ER -