FLCN regulates transferrin receptor 1 transport and iron homeostasis
| Autor: | Maozhen Qi, Yaping Jin, Wei Liu, Xiaojuan Wang, Lingling Zhao, Zeyao Liu, Hanjie Wu |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
HRE hypoxia response element Cytoplasm QIP quenchable iron pool GTPase-activating protein FLCN Endocytic recycling Biochemistry DMEM Dulbecco’s modified Eagle’s medium WB western blot Birt-Hogg-Dube Syndrome GAP GTPase-activating protein TfR1 transferrin receptor 1 Drosophila Proteins Homeostasis DENN differentially expressed in normal cells and neoplasia biology Chemistry Iron deficiency FITC-Tf fluorescence conjugated transferrin Cell biology HIF hypoxia-inducible factor BHD Drosophila melanogaster IRE iron-responsive element BHD Birt–Hogg–Dubé Models Animal Research Article Iron Transferrin receptor PHD prolyl hydroxylase PRC perinuclear recycling center DMT1 divalent metal transporter 1 03 medical and health sciences Antigens CD FLCN folliculin Proto-Oncogene Proteins Receptors Transferrin medicine HIF Animals Humans Folliculin Molecular Biology 030102 biochemistry & molecular biology co-IP coimmunoprecipitation Tumor Suppressor Proteins Binding protein Cell Biology DMT1 medicine.disease HEK293 Cells 030104 developmental biology rab GTP-Binding Proteins biology.protein RAB11A |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| DOI: | 10.1016/j.jbc.2021.100426 |
| Popis: | Birt-Hogg-Dubé (BHD) syndrome is a multiorgan disorder caused by inactivation of the folliculin (FLCN) protein. Previously, we identified FLCN as a binding protein of Rab11A, a key regulator of the endocytic recycling pathway. This finding implies that the abnormal localization of specific proteins whose transport requires the FLCN-Rab11A complex may contribute to BHD. Here, we used human kidney-derived HEK293 cells as a model, and we report that FLCN promotes the binding of Rab11A with transferrin receptor 1 (TfR1), which is required for iron uptake through continuous trafficking between the cell surface and the cytoplasm. Loss of FLCN attenuated the Rab11A-TfR1 interaction, resulting in delayed recycling transport of TfR1. This delay caused an iron deficiency condition that induced hypoxia-inducible factor (HIF) activity, which was reversed by iron supplementation. In a Drosophila model of BHD syndrome, we further demonstrated that the phenotype of BHD mutant larvae was substantially rescued by an iron-rich diet. These findings reveal a conserved function of FLCN in iron metabolism and may help to elucidate the mechanisms driving BHD syndrome. |
| Databáze: | OpenAIRE |
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