Human CIA2A-FAM96A and CIA2B-FAM96B integrate iron homeostasis and maturation of different subsets of cytosolic-nuclear iron-sulfur proteins.

Numerous cytosolic and nuclear proteins involved in metabolism, DNA maintenance, protein translation, or iron homeostasis depend on iron-sulfur (Fe/S) cofactors, yet their assembly is poorly defined. Here, we identify and characterize human CIA2A (FAM96A), CIA2B (FAM96B), and CIA1 (CIAO1) as components of the cytosolic Fe/S protein assembly (CIA) machinery. CIA1 associates with either CIA2A or CIA2B and the CIA-targeting factor MMS19. The CIA2B-CIA1-MMS19 complex binds to and facilitates assembly of most cytosolic-nuclear Fe/S proteins. In contrast, CIA2A specifically matures iron regulatory protein 1 (IRP1), which is critical for cellular iron homeostasis. Surprisingly, a second layer of iron regulation involves the stabilization of IRP2 by CIA2A binding or upon depletion of CIA2B or MMS19, even though IRP2 lacks an Fe/S cluster. In summary, CIA2B-CIA1-MMS19 and CIA2A-CIA1 assist different branches of Fe/S protein assembly and intimately link this process to cellular iron regulation via IRP1 Fe/S cluster maturation and IRP2 stabilization.
Mesh Terms:
Carrier Proteins, Cell Line, Tumor, Glycerol-3-Phosphate O-Acyltransferase, HeLa Cells, Homeostasis, Humans, Iron, Iron Regulatory Protein 1, Iron Regulatory Protein 2, Iron-Sulfur Proteins, Metallochaperones, Nuclear Proteins, Protein Binding, RNA Interference, RNA, Small Interfering, Transcription Factors
Cell Metab. Aug. 06, 2013; 18(2);187-98 [PUBMED:23891004]
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