دورية أكاديمية
A functional interplay between the two BMP-SMAD pathway inhibitors TMPRSS6 and FKBP12 regulates hepcidin expression in vivo.
| العنوان: | A functional interplay between the two BMP-SMAD pathway inhibitors TMPRSS6 and FKBP12 regulates hepcidin expression in vivo. |
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| المؤلفون: | Pettinato M; Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy.; San Raffaele Vita-Salute University, Milan, Italy., Aghajan M; Ionis Pharmaceuticals, Inc., Carlsbad, California, United States., Guo S; Ionis Pharmaceuticals, Inc., Carlsbad, California, United States., Bavuso Volpe L; Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy., Carleo R; Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy., Nai A; Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy.; San Raffaele Vita-Salute University, Milan, Italy., Pagani A; Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy.; San Raffaele Vita-Salute University, Milan, Italy., Altamura S; Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany., Silvestri L; Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy.; San Raffaele Vita-Salute University, Milan, Italy. |
| المصدر: | American journal of physiology. Gastrointestinal and liver physiology [Am J Physiol Gastrointest Liver Physiol] 2024 Mar 01; Vol. 326 (3), pp. G310-G317. Date of Electronic Publication: 2024 Jan 22. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901227 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1547 (Electronic) Linking ISSN: 01931857 NLM ISO Abbreviation: Am J Physiol Gastrointest Liver Physiol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Bethesda, MD : American Physiological Society |
| مواضيع طبية MeSH: | Hepcidins*/genetics , Hepcidins*/metabolism , Tacrolimus Binding Protein 1A*/genetics, Humans ; Iron/metabolism ; Membrane Proteins/genetics ; Serine ; Serine Endopeptidases/genetics ; Serine Proteases |
| مستخلص: | The Activin A Receptor type I (ALK2) is a critical component of BMP-SMAD signaling that, in the presence of ligands, phosphorylates cytosolic SMAD1/5/8 and modulates important biological processes, including bone formation and iron metabolism. In hepatocytes, the BMP-SMAD pathway controls the expression of hepcidin , the liver peptide hormone that regulates body iron homeostasis via the BMP receptors ALK2 and ALK3, and the hemochromatosis proteins. The main negative regulator of the pathway in the liver is transmembrane serine protease 6 (TMPRSS6), which downregulates hepcidin by cleaving the BMP coreceptor hemojuvelin. ALK2 function is inhibited also by the immunophilin FKBP12, which maintains the receptor in an inactive conformation. FKBP12 sequestration by tacrolimus or its silencing upregulates hepcidin in primary hepatocytes and in vivo in acute but not chronic settings. Interestingly, gain-of-function mutations in ALK2 that impair FKBP12 binding to the receptor and activate the pathway cause a bone phenotype in patients affected by Fibrodysplasia Ossificans Progressiva but not hepcidin and iron metabolism dysfunction. This observation suggests that additional mechanisms are active in the liver to compensate for the increased BMP-SMAD signaling. Here we demonstrate that Fkbp12 downregulation in hepatocytes by antisense oligonucleotide treatment upregulates the expression of the main hepcidin inhibitor Tmprss6, thus counteracting the ALK2-mediated activation of the pathway. Combined downregulation of both Fkbp12 and Tmprss6 blocks this compensatory mechanism. Our findings reveal a previously unrecognized functional cross talk between FKBP12 and TMPRSS6, the main BMP-SMAD pathway inhibitors, in the control of hepcidin transcription. NEW & NOTEWORTHY This study uncovers a previously unrecognized mechanism of hepcidin and BMP-SMAD pathway regulation in hepatocytes mediated by the immunophilin FKBP12 and the transmembrane serine protease TMPRSS6. |
| معلومات مُعتمدة: | GJC21117 Cariplo Telethon Alliance GJC2021; 1749055 Fondazione Regionale per la Ricerca Biomedica-FRRB; Advance Research Grant 2020 European Hematology Association (EHA); FOR5146 FerrOs |
| فهرسة مساهمة: | Keywords: ALK2; BMP-SMAD pathway; FKBP12; TMPRSS6; hepcidin |
| المشرفين على المادة: | 0 (Hepcidins) E1UOL152H7 (Iron) 0 (Membrane Proteins) 452VLY9402 (Serine) EC 3.4.21.- (Serine Endopeptidases) EC 3.4.- (Serine Proteases) EC 5.2.1.- (Tacrolimus Binding Protein 1A) EC 3.4.21.- (TMPRSS6 protein, human) 0 (HAMP protein, human) |
| تواريخ الأحداث: | Date Created: 20240122 Date Completed: 20240227 Latest Revision: 20240418 |
| رمز التحديث: | 20240418 |
| DOI: | 10.1152/ajpgi.00305.2023 |
| PMID: | 38252872 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1522-1547 |
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| DOI: | 10.1152/ajpgi.00305.2023 |