Hepatocyte proteomes reveal the role of protein disulfide isomerase 4 in alpha 1-antitrypsin deficiency
| Autor: | Jean-William Dupuy, Céline Léon, Frédéric Saltel, Sophie Collardeau-Frachon, Mathias Ruiz, Esra Karatas, Nathalie Senant, Marion Bouchecareilh, Sylvaine Di-Tommaso, Alain Lachaux, Anne-Aurélie Raymond |
|---|---|
| Přispěvatelé: | Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), BOUCHECAREILH, Marion |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
PDI
protein disulfide isomerase medicine.medical_treatment [SDV]Life Sciences [q-bio] PDIA3 protein disulfide isomerase family A member 3/ERP57 PDIA4 protein disulfide isomerase family A member 4/ERP70/ERP72 PDIA3 RC799-869 PDIA4 Liver transplantation Liver disease chemistry.chemical_compound 0302 clinical medicine ZZ homozygosis for the Z mutant allele NHK null Hong Kong variant of AAT Immunology and Allergy TXNDC5 thioredoxin domain containing 5/PDIA15 Protein disulfide-isomerase ComputingMilieux_MISCELLANEOUS Liver injury 0303 health sciences Alpha 1-antitrypsin deficiency Gastroenterology IP immunoprecipitation Scr scramble siRNA small RNA interference Diseases of the digestive system. Gastroenterology P4HB prolyl 4-hydroxylase subunit beta/PDIA1 3. Good health [SDV] Life Sciences [q-bio] FFPE formalin-fixed paraffin-embedded medicine.anatomical_structure TRX thioredoxin 030220 oncology & carcinogenesis Hepatocyte IHC immunohistochemistry Z-AAT alpha 1-antitrypsin Z variant Research Article Liver damage Cysteamine AAT alpha 1-antitrypsin AATD alpha 1-antitrypsin deficiency ER endoplasmic reticulum 03 medical and health sciences ROS reactive oxygen species Internal Medicine medicine CFTR cystic fibrosis transmembrane conductance regulator 030304 developmental biology CF cystic fibrosis Hepatology SURF4 proteins Surfeit 4 ΔF508-CFTR most common mutation of CFTR which deletes phenylalanine508 FKBP10 FK506-binding protein (FKBP) isoform 10 Protein disulfide isomerase medicine.disease WT wild-type Treatment chemistry Cancer research HCC hepatocellular carcinoma PDIi PDI inhibitors |
| Zdroj: | JHEP Reports JHEP Reports Innovation in Hepatology JHEP Reports Innovation in Hepatology, Elsevier, 2021, 3 (4), pp.100297. ⟨10.1016/j.jhepr.2021.100297⟩ JHEP Reports Innovation in Hepatology, 2021, 3 (4), pp.100297. ⟨10.1016/j.jhepr.2021.100297⟩ JHEP Reports, Vol 3, Iss 4, Pp 100297-(2021) |
| ISSN: | 2589-5559 |
| Popis: | Background & Aims A single point mutation in the Z-variant of alpha 1-antitrypsin (Z-AAT) alone can lead to both a protein folding and trafficking defect, preventing its exit from the endoplasmic reticulum (ER), and the formation of aggregates that are retained as inclusions within the ER of hepatocytes. These defects result in a systemic AAT deficiency (AATD) that causes lung disease, whereas the ER-retained aggregates can induce severe liver injury in patients with ZZ-AATD. Unfortunately, therapeutic approaches are still limited and liver transplantation represents the only curative treatment option. To overcome this limitation, a better understanding of the molecular basis of ER aggregate formation could provide new strategies for therapeutic intervention. Methods Our functional and omics approaches here based on human hepatocytes from patients with ZZ-AATD have enabled the identification and characterisation of the role of the protein disulfide isomerase (PDI) A4/ERP72 in features of AATD-mediated liver disease. Results We report that 4 members of the PDI family (PDIA4, PDIA3, P4HB, and TXNDC5) are specifically upregulated in ZZ-AATD liver samples from adult patients. Furthermore, we show that only PDIA4 knockdown or alteration of its activity by cysteamine treatment can promote Z-AAT secretion and lead to a marked decrease in Z aggregates. Finally, detailed analysis of the Z-AAT interactome shows that PDIA4 silencing provides a more conducive environment for folding of the Z mutant, accompanied by reduction of Z-AAT-mediated oxidative stress, a feature of AATD-mediated liver disease. Conclusions PDIA4 is involved in AATD-mediated liver disease and thus represents a therapeutic target for inhibition by drugs such as cysteamine. PDI inhibition therefore represents a potential therapeutic approach for treatment of AATD. Lay summary Protein disulfide isomerase (PDI) family members, and particularly PDIA4, are upregulated and involved in alpha 1-antitrypsin deficiency (AATD)-mediated liver disease in adults. PDI inhibition upon cysteamine treatment leads to improvements in features of AATD and hence represents a therapeutic approach for treatment of AATD-mediated liver disease. Graphical abstract Highlights • PDIA4 is upregulated and involved in alpha 1-antitrypsin deficiency (AATD)-mediated liver disease in adults. • Knockdown of PDIA4 by siRNA or inhibition upon cysteamine treatment leads to improvements in features of AATD. • RNA interference against PDIA4 or cysteamine represent approaches for treatment of AATD-mediated liver disease. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|