Lack of CFTR alters the ferret pancreatic ductal epithelial secretome and cellular proteome: Implications for exocrine/endocrine signaling.
Animals
Cystic Fibrosis
/ genetics
Cystic Fibrosis Transmembrane Conductance Regulator
/ genetics
Diabetes Mellitus
/ metabolism
Exocrine Pancreatic Insufficiency
/ metabolism
Ferrets
/ metabolism
Humans
Pancreas, Exocrine
/ metabolism
Pancreatic Ducts
/ metabolism
Proteome
/ metabolism
Secretome
/ metabolism
Cystic Fibrosis
Cystic Fibrosis Related Diabetes
ductal cells
pancreas
proteome
secretome
Journal
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
ISSN: 1873-5010
Titre abrégé: J Cyst Fibros
Pays: Netherlands
ID NLM: 101128966
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
31
01
2021
revised:
01
04
2021
accepted:
20
04
2021
pubmed:
22
5
2021
medline:
3
3
2022
entrez:
21
5
2021
Statut:
ppublish
Résumé
Cystic fibrosis (CF) related diabetes is the most common comorbidity for CF patients and associated with islet dysfunction. Exocrine pancreas remodeling in CF alters the microenvironment in which islets reside. Since CFTR is mainly expressed in pancreatic ductal epithelium, we hypothesized altered CF ductal secretions could impact islet function through paracrine signals. We evaluated the secretome and cellular proteome of polarized WT and CF ferret ductal epithelia using quantitative ratiometric mass spectrometry. Differentially secreted proteins (DSPs) or expressed cellular proteins were used to mine pathways, upstream regulators and the CFTR interactome to map candidate CF-associated alterations in ductal signaling and phenotype. Candidate DSPs were evaluated for their in vivo pancreatic expression patterns and their functional impact on islet hormone secretion. The secretome and cellular proteome of CF ductal epithelia was significantly altered relative to WT and implicated dysregulated TGFβ, WNT, and BMP signaling pathways. Cognate receptors of DSPs from CF epithelia were equally distributed among endocrine, exocrine, and stromal pancreatic cell types. IGFBP7 was a downregulated DSP in CF ductal epithelia in vitro and exhibited reduced CF ductal expression in vivo. IGFBP7 also altered WT islet insulin secretion in response to glucose. Many CFTR-associated proteins, including SLC9A3R1, were differentially expressed in the CF cellular proteome. Upstream regulators of the differential CF ductal proteome included TGFβ, PDX1, AKT/PTEN, and INSR signaling. Data is available via ProteomeXchange with identifier PXD025126. These findings provide a proteomic roadmap for elucidating disturbances in autocrine and paracrine signals from CF pancreatic ducts and how they may alter islet function and maintenance.
Sections du résumé
BACKGROUND
Cystic fibrosis (CF) related diabetes is the most common comorbidity for CF patients and associated with islet dysfunction. Exocrine pancreas remodeling in CF alters the microenvironment in which islets reside. Since CFTR is mainly expressed in pancreatic ductal epithelium, we hypothesized altered CF ductal secretions could impact islet function through paracrine signals.
METHOD
We evaluated the secretome and cellular proteome of polarized WT and CF ferret ductal epithelia using quantitative ratiometric mass spectrometry. Differentially secreted proteins (DSPs) or expressed cellular proteins were used to mine pathways, upstream regulators and the CFTR interactome to map candidate CF-associated alterations in ductal signaling and phenotype. Candidate DSPs were evaluated for their in vivo pancreatic expression patterns and their functional impact on islet hormone secretion.
RESULTS
The secretome and cellular proteome of CF ductal epithelia was significantly altered relative to WT and implicated dysregulated TGFβ, WNT, and BMP signaling pathways. Cognate receptors of DSPs from CF epithelia were equally distributed among endocrine, exocrine, and stromal pancreatic cell types. IGFBP7 was a downregulated DSP in CF ductal epithelia in vitro and exhibited reduced CF ductal expression in vivo. IGFBP7 also altered WT islet insulin secretion in response to glucose. Many CFTR-associated proteins, including SLC9A3R1, were differentially expressed in the CF cellular proteome. Upstream regulators of the differential CF ductal proteome included TGFβ, PDX1, AKT/PTEN, and INSR signaling. Data is available via ProteomeXchange with identifier PXD025126.
CONCLUSION
These findings provide a proteomic roadmap for elucidating disturbances in autocrine and paracrine signals from CF pancreatic ducts and how they may alter islet function and maintenance.
Identifiants
pubmed: 34016558
pii: S1569-1993(21)00120-X
doi: 10.1016/j.jcf.2021.04.010
pmc: PMC8595456
mid: NIHMS1705811
pii:
doi:
Substances chimiques
CFTR protein, human
0
Proteome
0
Cystic Fibrosis Transmembrane Conductance Regulator
126880-72-6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
172-180Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK054759
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK097820
Pays : United States
Organisme : NIDDK NIH HHS
ID : RC2 DK124207
Pays : United States
Informations de copyright
Copyright © 2021. Published by Elsevier B.V.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare no existing conflicts of interest.
Références
Sci Rep. 2020 Oct 16;10(1):17581
pubmed: 33067534
Carcinogenesis. 2013 Sep;34(9):1943-54
pubmed: 23671130
J Clin Invest. 2012 Oct;122(10):3755-68
pubmed: 22996690
Immunity. 2015 Oct 20;43(4):690-702
pubmed: 26410627
Endocrinology. 2016 May;157(5):1852-65
pubmed: 26862997
J Clin Med. 2019 Nov 06;8(11):
pubmed: 31698802
Cancer Cell. 2005 Sep;8(3):185-95
pubmed: 16169464
Diabetologia. 2012 Dec;55(12):3331-40
pubmed: 22926403
Cold Spring Harb Perspect Med. 2013 May 01;3(5):a009746
pubmed: 23637307
Cell. 2019 Feb 7;176(4):790-804.e13
pubmed: 30661759
J Clin Invest. 2020 Aug 3;130(8):3974-3986
pubmed: 32407294
J Biol Chem. 2012 May 18;287(21):17016-17028
pubmed: 22453918
Endocrinology. 2017 Oct 1;158(10):3325-3338
pubmed: 28977592
Am J Respir Crit Care Med. 2016 Oct 15;194(8):974-980
pubmed: 27447840
Sci Transl Med. 2019 Jul 3;11(499):
pubmed: 31270271
Development. 2017 Aug 15;144(16):2873-2888
pubmed: 28811309
Redox Biol. 2013 Feb 05;1:190-202
pubmed: 24024153
Cell Mol Gastroenterol Hepatol. 2017 Dec 07;5(3):253-271
pubmed: 29675451
Diabetes Care. 2009 Sep;32(9):1626-31
pubmed: 19542209
Am J Pathol. 2018 Apr;188(4):876-890
pubmed: 29366680
Eur J Endocrinol. 2004 Aug;151 Suppl 1:S77-80
pubmed: 15339249
Endocrinology. 2016 Jul;157(7):2649-59
pubmed: 27167773
Cell Rep. 2019 Feb 12;26(7):1951-1964.e8
pubmed: 30759402
EMBO J. 2003 May 1;22(9):1981-9
pubmed: 12727866
J Clin Invest. 2009 Mar;119(3):540-50
pubmed: 19221439
Lancet. 2016 Nov 19;388(10059):2519-2531
pubmed: 27140670
Cell Death Dis. 2015 Jan 15;6:e1591
pubmed: 25590801
J Endocrinol. 2019 Feb 1;:
pubmed: 30759072
PLoS One. 2013 Jun 28;8(6):e68253
pubmed: 23840838
Endocr Dev. 2007;12:33-45
pubmed: 17923767