An Oxygen-Dependent Interaction between FBXL5 and the CIA-Targeting Complex Regulates Iron Homeostasis

• Published in: Molecular cell Vol. 75; no. 2; pp. 382 - 393.e5
• Main Authors: Mayank, Adarsh K., Pandey, Vijaya, Vashisht, Ajay A., Barshop, William D., Rayatpisheh, Shima, Sharma, Tanu, Haque, Tisha, Powers, David N., Wohlschlegel, James A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.07.2019
• Subjects: Cell Cycle Proteins - chemistry; Cell Cycle Proteins - genetics; CIA-targeting complex; CIAO1; F-Box Proteins - chemistry; F-Box Proteins - genetics; FAM96B; FBXL5; HeLa Cells; Homeostasis; Humans; hypoxia; Iron - metabolism; iron homeostasis; Iron-Regulatory Proteins - genetics; Iron-Sulfur Proteins - chemistry; Iron-Sulfur Proteins - genetics; IRP1; IRP2; MMS19; Molecular Chaperones - chemistry; Molecular Chaperones - genetics; Multiprotein Complexes - chemistry; Multiprotein Complexes - genetics; Oxygen - metabolism; Proteolysis; Transcription Factors - genetics; Ubiquitin-Protein Ligase Complexes - chemistry; Ubiquitin-Protein Ligase Complexes - genetics; iron metabolism; hypoxia; iron homeostasis; IRP1; FAM96B; CIA-targeting complex; IRP2; MMS19; FBXL5; CIAO1
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2019.05.020

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 (O2) tension displaying a robust association in 21% O2 that is severely diminished in 1% O2 and contributes to O2-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. [Display omitted] •The CIA-targeting complex interacts with, but is not a substrate of, FBXL5•The CTBD domain of FBXL5 is critical for interaction with the CIA-targeting complex•The CIA-targeting complex stimulates FBXL5-mediated polyubiquitination of IRPs•O2 levels regulate the FBXL5-CIA-targeting complex interaction Mayank et al. describe a mechanism of crosstalk between the iron homeostasis and Fe-S cluster biogenesis pathways that is mediated by an interaction between the iron sensor FBXL5 and the CIA-targeting complex, which assembles cofactors on cytosolic proteins. This mechanism is required for the proper regulation of these pathways.