Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Mol Cell. 2019 Jul 25;75(2):382-393.e5. doi: 10.1016/j.molcel.2019.05.020. Epub 2019 Jun 19.
The iron-sensing protein FBXL5 is the substrate adaptor for a SKP1-CUL1-RBX1 E3 ubiquitin ligase complex that regulates the degradation of iron regulatory proteins (IRPs). Here, we describe a mechanism of FBXL5 regulation involving its interaction with the cytosolic Fe-S cluster assembly (CIA) targeting complex composed of MMS19, FAM96B, and CIAO1. We demonstrate that the CIA-targeting complex promotes the ability of FBXL5 to degrade IRPs. In addition, the FBXL5-CIA-targeting complex interaction is regulated by oxygen (O) tension displaying a robust association in 21% O that is severely diminished in 1% O and contributes to O-dependent regulation of IRP degradation. Together, these data identify a novel oxygen-dependent signaling axis that links IRP-dependent iron homeostasis with the Fe-S cluster assembly machinery.
铁感应蛋白 FBXL5 是 SKP1-CUL1-RBX1 E3 泛素连接酶复合物的底物衔接蛋白,该复合物调节铁调节蛋白 (IRP) 的降解。在这里,我们描述了一种涉及 FBXL5 与其与胞质 Fe-S 簇组装 (CIA) 靶向复合物相互作用的调节机制,该复合物由 MMS19、FAM96B 和 CIAO1 组成。我们证明 CIA 靶向复合物促进了 FBXL5 降解 IRP 的能力。此外,FBXL5-CIA 靶向复合物相互作用受氧 (O) 张力的调节,在 21%O 下表现出强烈的关联,在 1%O 下严重减弱,并有助于 IRP 降解的 O 依赖性调节。总之,这些数据确定了一个新的氧依赖性信号轴,它将 IRP 依赖性铁稳态与 Fe-S 簇组装机制联系起来。