دورية أكاديمية
FKBP12 inhibits hepcidin expression by modulating BMP receptors interaction and ligand responsiveness in hepatocytes.
| العنوان: | FKBP12 inhibits hepcidin expression by modulating BMP receptors interaction and ligand responsiveness in hepatocytes. |
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| المؤلفون: | Pettinato M; Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy., Dulja A; Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy., Colucci S; Department of Pediatric Hematology, Oncology and Immunology, Center for Translational Biomedical Iron Research - University of Heidelberg & Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany., Furiosi V; Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy., Fette F; Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Johann-Wolfgang-Goethe University Frankfurt, Frankfurt am Main, Germany., Steinbicker AU; Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Johann-Wolfgang-Goethe University Frankfurt, Frankfurt am Main, Germany., Muckenthaler MU; Department of Pediatric Hematology, Oncology and Immunology, Center for Translational Biomedical Iron Research - University of Heidelberg & Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany., Nai A; Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy.; School of Medicine, Vita-Salute San Raffaele University, Milan, Italy., Pagani A; Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy., Silvestri L; Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy.; School of Medicine, Vita-Salute San Raffaele University, Milan, Italy. |
| المصدر: | American journal of hematology [Am J Hematol] 2023 Aug; Vol. 98 (8), pp. 1223-1235. Date of Electronic Publication: 2023 May 18. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Wiley-Blackwell Country of Publication: United States NLM ID: 7610369 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-8652 (Electronic) Linking ISSN: 03618609 NLM ISO Abbreviation: Am J Hematol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: New York Ny : Wiley-Blackwell Original Publication: New York, Liss. |
| مواضيع طبية MeSH: | Hepcidins*/genetics , Hepcidins*/metabolism , Tacrolimus Binding Protein 1A*/genetics , Tacrolimus Binding Protein 1A*/metabolism, Humans ; Mice ; Animals ; Ligands ; Bone Morphogenetic Protein Receptors/metabolism ; Hepatocytes/metabolism ; Bone Morphogenetic Protein 6/genetics |
| مستخلص: | The expression of the iron regulatory hormone hepcidin in hepatocytes is regulated by the BMP-SMAD pathway through the type I receptors ALK2 and ALK3, the type II receptors ACVR2A and BMPR2, and the ligands BMP2 and BMP6. We previously identified the immunophilin FKBP12 as a new hepcidin inhibitor that acts by blocking ALK2. Both the physiologic ALK2 ligand BMP6 and the immunosuppressive drug Tacrolimus (TAC) displace FKBP12 from ALK2 and activate the signaling. However, the molecular mechanism whereby FKBP12 regulates BMP-SMAD pathway activity and thus hepcidin expression remains unclear. Here, we show that FKBP12 acts by modulating BMP receptor interactions and ligand responsiveness. We first demonstrate that in primary murine hepatocytes TAC regulates hepcidin expression exclusively via FKBP12. Downregulation of the BMP receptors reveals that ALK2, to a lesser extent ALK3, and ACVR2A are required for hepcidin upregulation in response to both BMP6 and TAC. Mechanistically, TAC and BMP6 increase ALK2 homo-oligomerization and ALK2-ALK3 hetero-oligomerization and the interaction between ALK2 and the type II receptors. By acting on the same receptors, TAC and BMP6 cooperate in BMP pathway activation and hepcidin expression both in vitro and in vivo. Interestingly, the activation state of ALK3 modulates its interaction with FKBP12, which may explain the cell-specific activity of FKBP12. Overall, our results identify the mechanism whereby FKBP12 regulates the BMP-SMAD pathway and hepcidin expression in hepatocytes, and suggest that FKBP12-ALK2 interaction is a potential pharmacologic target in disorders caused by defective BMP-SMAD signaling and characterized by low hepcidin and high BMP6 expression. (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.) |
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| المشرفين على المادة: | 0 (Hepcidins) EC 5.2.1.- (Tacrolimus Binding Protein 1A) 0 (Ligands) EC 2.7.11.30 (Bone Morphogenetic Protein Receptors) 0 (Bone Morphogenetic Protein 6) |
| تواريخ الأحداث: | Date Created: 20230518 Date Completed: 20230713 Latest Revision: 20230718 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1002/ajh.26961 |
| PMID: | 37199280 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1096-8652 |
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| DOI: | 10.1002/ajh.26961 |