College of Veterinary Medicine, Northwest A&F University, Yangling, Shanxi, China.
College of Veterinary Medicine, Northwest A&F University, Yangling, Shanxi, China.
J Biol Chem. 2021 Jan-Jun;296:100426. doi: 10.1016/j.jbc.2021.100426. Epub 2021 Feb 17.
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.
Birt-Hogg-Dubé (BHD) 综合征是一种多器官疾病，由滤泡素 (FLCN) 蛋白失活引起。此前，我们鉴定出 FLCN 是 Rab11A 的结合蛋白，Rab11A 是内吞体循环途径的关键调节因子。这一发现表明，需要 FLCN-Rab11A 复合物运输的特定蛋白质的异常定位可能导致 BHD。在这里，我们使用人肾源性 HEK293 细胞作为模型，报告 FLCN 促进 Rab11A 与转铁蛋白受体 1 (TfR1) 的结合，这是通过细胞表面和细胞质之间的连续运输摄取铁所必需的。FLCN 的缺失减弱了 Rab11A-TfR1 的相互作用，导致 TfR1 的回收运输延迟。这种延迟导致铁缺乏条件，诱导缺氧诱导因子 (HIF) 活性，而铁补充可逆转这种活性。在 BHD 综合征的果蝇模型中，我们进一步证明，富含铁的饮食可显著挽救 BHD 突变体幼虫的表型。这些发现揭示了 FLCN 在铁代谢中的保守功能，并可能有助于阐明驱动 BHD 综合征的机制。
