PDF(Pubmed)
Abstract：
To ensure proper utilization of iron and avoid its toxicity, cells are equipped with iron-sensing proteins to maintain cellular iron homeostasis. We showed previously that nuclear receptor coactivator 4 (NCOA4), a ferritin-specific autophagy adapter, intricately regulates the fate of ferritin; upon binding to Fe3+, NCOA4 forms insoluble condensates and regulates ferritin autophagy in iron-replete conditions. Here, we demonstrate an additional iron-sensing mechanism of NCOA4. Our results indicate that the insertion of an iron-sulfur (Fe-S) cluster enables preferential recognition of NCOA4 by the HERC2 (HECT and RLD domain containing E3 ubiquitin protein ligase 2) ubiquitin ligase in iron-replete conditions, resulting in degradation by the proteasome and subsequent inhibition of ferritinophagy. We also found that both condensation and ubiquitin-mediated degradation of NCOA4 can occur in the same cell, and the cellular oxygen tension determines the selection of these pathways. Fe-S cluster-mediated degradation of NCOA4 is enhanced under hypoxia, whereas NCOA4 forms condensates and degrades ferritin at higher oxygen levels. Considering the involvement of iron in oxygen handling, our findings demonstrate that the NCOA4-ferritin axis is another layer of cellular iron regulation in response to oxygen levels.
摘要：
为了确保适当利用铁并避免其毒性，细胞配备了铁感应蛋白以维持细胞铁稳态。我们之前表明，NCOA4是一种铁蛋白特异性自噬适配器，复杂地调节铁蛋白的命运；在与Fe3+结合时，NCOA4在铁充足的条件下形成不溶性缩合物并调节铁蛋白自噬。这里,我们证明了NCOA4的另一种铁感应机制。我们的结果表明，Fe-S簇的插入能够在铁充足的条件下通过HERC2泛素连接酶优先识别NCOA4，导致蛋白酶体降解，随后抑制铁素吞噬。我们还发现，NCOA4的缩合和泛素介导的降解都可以在同一细胞中发生，细胞氧张力决定了这些途径的选择。缺氧条件下Fe-S簇介导的NCOA4降解增强,而NCOA4在较高的氧气水平下形成冷凝物并降解铁蛋白。考虑到铁参与氧气处理，我们的研究结果表明，NCOA4/铁蛋白轴是响应氧水平的细胞铁调节的另一层。
