Human CIA2A-FAM96A and CIA2B-FAM96B Integrate Iron Homeostasis and Maturation of Different Subsets of Cytosolic-Nuclear Iron-Sulfur Proteins

Abstract

SUMMARY 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 (IRP) 1 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 a 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.

Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity

“…The Fbxw2 gene encodes an F-box and WD-40 domain protein and has been shown to positively regulate ubiquitination of hGCM1, a zinc-containing transcription factor involved in placental and parathyroid development (70,71). The protein encoded by Eepd1 is known to interact with CIA1 (cytosolic iron-sulfur protein assembly component 1) and potentially contribute to the maturation of Fe/S proteins (72). These genes are involved in different biological processes, showing the complexity of molecular mechanisms underlying obesity.…”

Glutaredoxin GRXS17 Associates with the Cytosolic Iron-Sulfur Cluster Assembly Pathway

“…Numbers of independent TAP experiments in which the proteins were copurified with C terminally or N terminally TAP-tagged GRXS17 as bait in each system are presented. Interactions that were confirmed in yeast (Tarassov et al, 2008;Li et al, 2009;Zhang et al, 2011), in humans (Rual et al, 2005;Stehling et al, 2012Stehling et al, , 2013Rolland et al, 2014), or in Arabidopsis (this study; Arabidopsis Interactome Mapping, 2011; Couturier et al, 2014;Duan et al, 2015) are shown in bold. GSrh, GSrhino; Nd, Not determined; *, peptides retrieved cannot discriminate between CTU1 and CTU1L.…”

A multi-target protein of hTERTR-FAM96A presents significant anticancer potent in the treatment of hepatocellular carcinoma

“…15 Stehling et al 14 showed that FAM96A is involved in metabolism, DNA maintenance, and protein translation, facilitating the effective induction of cell death via the mitochondrial apoptosis pathway by binding pro-apoptotic Apaf-1 protein, yet it is poorly expressed in most of tumor cells. FAM96A, as a pro-apoptotic tumor suppressor, presented therapeutic effects for tumor cells.…”

“…[14][15][16] FAM96A was described as a novel pro-apoptotic tumor suppressor and has therapeutic effects in gastrointestinal stromal tumors in vitro and in vivo. 17 In addition, the expression of FAM96A was decreased in HCC cells.…”