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EMC6 regulates acinar apoptosis via APAF1 in acute and chronic pancreatitis
Treatment of acute pancreatitis (AP) and chronic pancreatitis (CP) remains problematic due to a lack of knowledge about disease-specific regulatory targets and mechanisms. The purpose of this study was to screen proteins related to endoplasmic reticulum (ER) stress and apoptosis pathways that may pl...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658364/ https://www.ncbi.nlm.nih.gov/pubmed/33177505 http://dx.doi.org/10.1038/s41419-020-03177-3 |
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author | Tan, Jie-hui Cao, Rong-chang Zhou, Lei Zhou, Zhi-tao Chen, Huo-ji Xu, Jia Chen, Xue-mei Jin, Yang-chen Lin, Jia-yu Qi, Zhao-chang Zeng, Jun-ling Li, Shu-ji Luo, Min Hu, Guo-dong Jin, Jin Zhang, Guo-wei |
author_facet | Tan, Jie-hui Cao, Rong-chang Zhou, Lei Zhou, Zhi-tao Chen, Huo-ji Xu, Jia Chen, Xue-mei Jin, Yang-chen Lin, Jia-yu Qi, Zhao-chang Zeng, Jun-ling Li, Shu-ji Luo, Min Hu, Guo-dong Jin, Jin Zhang, Guo-wei |
author_sort | Tan, Jie-hui |
collection | PubMed |
description | Treatment of acute pancreatitis (AP) and chronic pancreatitis (CP) remains problematic due to a lack of knowledge about disease-specific regulatory targets and mechanisms. The purpose of this study was to screen proteins related to endoplasmic reticulum (ER) stress and apoptosis pathways that may play a role in pancreatitis. Human pancreatic tissues including AP, CP, and healthy volunteers were collected during surgery. Humanized PRSS1 (protease serine 1) transgenic (PRSS1(Tg)) mice were constructed and treated with caerulein to mimic the development of human AP and CP. Potential regulatory proteins in pancreatitis were identified by proteomic screen using pancreatic tissues of PRSS1(Tg) AP mice. Adenoviral shRNA-mediated knockdown of identified proteins, followed by functional assays was performed to validate their roles. Functional analyses included transmission electron microscopy for ultrastructural analysis; qRT-PCR, western blotting, co-immunoprecipitation, immunohistochemistry, and immunofluorescence for assessment of gene or protein expression, and TUNEL assays for assessment of acinar cell apoptosis. Humanized PRSS1(Tg) mice could mimic the development of human pancreatic inflammatory diseases. EMC6 and APAF1 were identified as potential regulatory molecules in AP and CP models by proteomic analysis. Both EMC6 and APAF1 regulated apoptosis and inflammatory injury in pancreatic inflammatory diseases. Moreover, APAF1 was regulated by EMC6, induced apoptosis to injure acinar cells and promoted inflammation. In the progression of pancreatitis, EMC6 was activated and then upregulated APAF1 to induce acinar cell apoptosis and inflammatory injury. These findings suggest that EMC6 may be a new therapeutic target for the treatment of pancreatic inflammatory diseases. |
format | Online Article Text |
id | pubmed-7658364 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-76583642020-11-17 EMC6 regulates acinar apoptosis via APAF1 in acute and chronic pancreatitis Tan, Jie-hui Cao, Rong-chang Zhou, Lei Zhou, Zhi-tao Chen, Huo-ji Xu, Jia Chen, Xue-mei Jin, Yang-chen Lin, Jia-yu Qi, Zhao-chang Zeng, Jun-ling Li, Shu-ji Luo, Min Hu, Guo-dong Jin, Jin Zhang, Guo-wei Cell Death Dis Article Treatment of acute pancreatitis (AP) and chronic pancreatitis (CP) remains problematic due to a lack of knowledge about disease-specific regulatory targets and mechanisms. The purpose of this study was to screen proteins related to endoplasmic reticulum (ER) stress and apoptosis pathways that may play a role in pancreatitis. Human pancreatic tissues including AP, CP, and healthy volunteers were collected during surgery. Humanized PRSS1 (protease serine 1) transgenic (PRSS1(Tg)) mice were constructed and treated with caerulein to mimic the development of human AP and CP. Potential regulatory proteins in pancreatitis were identified by proteomic screen using pancreatic tissues of PRSS1(Tg) AP mice. Adenoviral shRNA-mediated knockdown of identified proteins, followed by functional assays was performed to validate their roles. Functional analyses included transmission electron microscopy for ultrastructural analysis; qRT-PCR, western blotting, co-immunoprecipitation, immunohistochemistry, and immunofluorescence for assessment of gene or protein expression, and TUNEL assays for assessment of acinar cell apoptosis. Humanized PRSS1(Tg) mice could mimic the development of human pancreatic inflammatory diseases. EMC6 and APAF1 were identified as potential regulatory molecules in AP and CP models by proteomic analysis. Both EMC6 and APAF1 regulated apoptosis and inflammatory injury in pancreatic inflammatory diseases. Moreover, APAF1 was regulated by EMC6, induced apoptosis to injure acinar cells and promoted inflammation. In the progression of pancreatitis, EMC6 was activated and then upregulated APAF1 to induce acinar cell apoptosis and inflammatory injury. These findings suggest that EMC6 may be a new therapeutic target for the treatment of pancreatic inflammatory diseases. Nature Publishing Group UK 2020-11-11 /pmc/articles/PMC7658364/ /pubmed/33177505 http://dx.doi.org/10.1038/s41419-020-03177-3 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Tan, Jie-hui Cao, Rong-chang Zhou, Lei Zhou, Zhi-tao Chen, Huo-ji Xu, Jia Chen, Xue-mei Jin, Yang-chen Lin, Jia-yu Qi, Zhao-chang Zeng, Jun-ling Li, Shu-ji Luo, Min Hu, Guo-dong Jin, Jin Zhang, Guo-wei EMC6 regulates acinar apoptosis via APAF1 in acute and chronic pancreatitis |
title | EMC6 regulates acinar apoptosis via APAF1 in acute and chronic pancreatitis |
title_full | EMC6 regulates acinar apoptosis via APAF1 in acute and chronic pancreatitis |
title_fullStr | EMC6 regulates acinar apoptosis via APAF1 in acute and chronic pancreatitis |
title_full_unstemmed | EMC6 regulates acinar apoptosis via APAF1 in acute and chronic pancreatitis |
title_short | EMC6 regulates acinar apoptosis via APAF1 in acute and chronic pancreatitis |
title_sort | emc6 regulates acinar apoptosis via apaf1 in acute and chronic pancreatitis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658364/ https://www.ncbi.nlm.nih.gov/pubmed/33177505 http://dx.doi.org/10.1038/s41419-020-03177-3 |
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