p-STAT3 is a PDC-E2 interacting partner in human cholangiocytes and hepatocytes with potential pathobiological implications.
Autoantigens
/ metabolism
Bile Ducts
/ pathology
Cell Line
Dihydrolipoyllysine-Residue Acetyltransferase
/ metabolism
Epithelial Cells
/ metabolism
Glycochenodeoxycholic Acid
/ pharmacology
Hep G2 Cells
Hepatocytes
/ metabolism
Humans
Immunoblotting
/ methods
Immunoprecipitation
/ methods
Liver
/ pathology
Liver Cirrhosis, Biliary
/ metabolism
Mitochondria
/ metabolism
Mitochondrial Proteins
/ metabolism
Pyruvate Dehydrogenase Complex
/ metabolism
STAT3 Transcription Factor
/ metabolism
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
04 11 2021
04 11 2021
Historique:
received:
25
03
2021
accepted:
22
10
2021
entrez:
5
11
2021
pubmed:
6
11
2021
medline:
27
1
2022
Statut:
epublish
Résumé
The E2 component of the mitochondrial pyruvate dehydrogenase complex (PDC) is the key autoantigen in primary biliary cholangitis (PBC) and STAT3 is an inflammatory modulator that participates in the pathogenesis of many liver diseases. This study investigated whether PDC-E2 interacts with STAT3 in human cholangiocytes (NHC) and hepatocytes (Hep-G2) under cholestatic conditions induced by glyco-chenodeoxycholic acid (GCDC). GCDC induced PDC-E2 expression in the cytoplasmic and nuclear fraction of NHC, whereas in Hep-G2 cells PDC-E2 expression was induced only in the cytoplasmic fraction. GCDC-treatment stimulated phosphorylation of STAT3 in the cytoplasmic fraction of NHC. siRNA-mediated gene silencing of PDC-E2 reduced the expression of pY-STAT3 in NHC but not in HepG2 cells. Immunoprecipitation and a proximity ligation assay clearly demonstrated that GCDC enhanced pY-STAT3 binding to PDC-E2 in the nuclear and cytoplasmic fraction of NHC cells. Staining with Mitotracker revealed mitochondrial co-localization of PDC-E2/pS-STAT3 complexes in NHC and Hep-G2 cells. In cirrhotic PBC livers the higher expression of both PDC-E2 and pY-STAT3 was observed. The immunoblot analysis demonstrated the occurrence of double bands of PDC-E2 protein in control livers, which was associated with a lower expression of pY-STAT3. Our data indicate the interaction between PDC-E2 and phosphorylated STAT3 under cholestatic conditions, which may play a role in the development of PBC.
Identifiants
pubmed: 34737337
doi: 10.1038/s41598-021-01060-5
pii: 10.1038/s41598-021-01060-5
pmc: PMC8569217
doi:
Substances chimiques
Autoantigens
0
Mitochondrial Proteins
0
Pyruvate Dehydrogenase Complex
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
Glycochenodeoxycholic Acid
640-79-9
DLAT protein, human
EC 2.3.1.12
Dihydrolipoyllysine-Residue Acetyltransferase
EC 2.3.1.12
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
21649Subventions
Organisme : National Science Centre
ID : 2017/25/B/NZ5/00819
Informations de copyright
© 2021. The Author(s).
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