University of Alberta, Faculty of Science, Edmonton, Alberta, T6G 2E9, Canada.
Stanford Synchrotron Radiation Lightsource SLAC National Accelerator Laboratory, 2575 Sand Hill Road, Menlo Park, CA, 94025, USA.
Nat Commun. 2024 May 14;15(1):4045. doi: 10.1038/s41467-024-48165-9.
Vesicular transport is essential for delivering cargo to intracellular destinations. Evi5 is a Rab11-GTPase-activating protein involved in endosome recycling. In humans, Evi5 is a high-risk locus for multiple sclerosis, a debilitating disease that also presents with excess iron in the CNS. In insects, the prothoracic gland (PG) requires entry of extracellular iron to synthesize steroidogenic enzyme cofactors. The mechanism of peripheral iron uptake in insect cells remains controversial. We show that Evi5-depletion in the Drosophila PG affected vesicle morphology and density, blocked endosome recycling and impaired trafficking of transferrin-1, thus disrupting heme synthesis due to reduced cellular iron concentrations. We show that ferritin delivers iron to the PG as well, and interacts physically with Evi5. Further, ferritin-injection rescued developmental delays associated with Evi5-depletion. To summarize, our findings show that Evi5 is critical for intracellular iron trafficking via transferrin-1 and ferritin, and implicate altered iron homeostasis in the etiology of multiple sclerosis.
囊泡运输对于将货物输送到细胞内目的地至关重要。Evi5 是一种参与内体再循环的 Rab11-GTPase 激活蛋白。在人类中，Evi5 是多发性硬化症的高风险基因座，多发性硬化症是一种使人衰弱的疾病，中枢神经系统中也存在过量的铁。在昆虫中，前胸腺 (PG) 需要进入细胞外铁来合成甾体激素酶辅因子。昆虫细胞中周围铁摄取的机制仍存在争议。我们表明，果蝇 PG 中的 Evi5 耗竭会影响囊泡形态和密度，阻断内体再循环并损害转铁蛋白 1 的运输，从而由于细胞内铁浓度降低而破坏血红素合成。我们表明铁蛋白也将铁递送到 PG，并与 Evi5 发生物理相互作用。此外，铁蛋白注射可挽救与 Evi5 耗竭相关的发育迟缓。总之，我们的研究结果表明，Evi5 通过转铁蛋白 1 和铁蛋白对细胞内铁运输至关重要，并表明多发性硬化症的发病机制与铁稳态改变有关。
