Laboratory for Molecular Nutrition, Faculty of Biotechnology and Food Engineering, Technion, Technion City, Haifa, Israel.
Center for Medical Genetics, Beijing Children's Hospital, Capital Medical University, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Beijing, China.
Blood. 2018 Jan 18;131(3):342-352. doi: 10.1182/blood-2017-02-768580. Epub 2017 Oct 26.
Ferritin turnover plays a major role in tissue iron homeostasis, and ferritin malfunction is associated with impaired iron homeostasis and neurodegenerative diseases. In most eukaryotes, ferritin is considered an intracellular protein that stores iron in a nontoxic and bioavailable form. In insects, ferritin is a classically secreted protein and plays a major role in systemic iron distribution. Mammalian ferritin lacks the signal peptide for classical endoplasmic reticulum-Golgi secretion but is found in serum and is secreted via a nonclassical lysosomal secretion pathway. This study applied bioinformatics and biochemical tools, alongside a protein trafficking mouse models, to characterize the mechanisms of ferritin secretion. Ferritin trafficking via the classical secretion pathway was ruled out, and a 2:1 distribution of intracellular ferritin between membrane-bound compartments and the cytosol was observed, suggesting a role for ferritin in the vesicular compartments of the cell. Focusing on nonclassical secretion, we analyzed mouse models of impaired endolysosomal trafficking and found that ferritin secretion was decreased by a BLOC-1 mutation but increased by BLOC-2, BLOC-3, and Rab27A mutations of the cellular trafficking machinery, suggesting multiple export routes. A 13-amino-acid motif unique to ferritins that lack the secretion signal peptide was identified on the BC-loop of both subunits and plays a role in the regulation of ferritin secretion. Finally, we provide evidence that secretion of iron-rich ferritin was mediated via the multivesicular body-exosome pathway. These results enhance our understanding of the mechanism of ferritin secretion, which is an important piece in the puzzle of tissue iron homeostasis.
铁蛋白周转率在组织铁稳态中起着重要作用，铁蛋白功能障碍与铁稳态受损和神经退行性疾病有关。在大多数真核生物中，铁蛋白被认为是一种细胞内蛋白，以无毒和可利用的形式储存铁。在昆虫中，铁蛋白是一种经典的分泌蛋白，在全身铁分布中起着重要作用。哺乳动物铁蛋白缺乏经典内质网-高尔基体分泌的信号肽，但存在于血清中，并通过非经典溶酶体分泌途径分泌。本研究应用生物信息学和生化工具，以及蛋白质转运小鼠模型，来描述铁蛋白分泌的机制。铁蛋白通过经典分泌途径的转运被排除，并且观察到细胞内铁蛋白在膜结合隔室和细胞质之间的 2:1 分布，表明铁蛋白在细胞的囊泡隔室中发挥作用。关注非经典分泌，我们分析了内体溶酶体运输受损的小鼠模型，发现铁蛋白分泌被 BLOC-1 突变减少，但被细胞运输机制的 BLOC-2、BLOC-3 和 Rab27A 突变增加，表明存在多种出口途径。在缺乏分泌信号肽的铁蛋白的 BC 环上鉴定到一个 13 个氨基酸的独特模体，该模体在铁蛋白分泌的调节中发挥作用。最后，我们提供了证据表明富含铁的铁蛋白的分泌是通过多泡体-外泌体途径介导的。这些结果增强了我们对铁蛋白分泌机制的理解，这是组织铁稳态之谜中的重要一环。
