CIAO1

Last update 23 Jan 2025

Basic Info

Synonyms

CIA1, CIAO1, cytosolic iron-sulfur assembly component 1

+ [3]

Introduction

Key component of the cytosolic iron-sulfur protein assembly (CIA) complex, a multiprotein complex that mediates the incorporation of iron-sulfur cluster into extramitochondrial Fe/S proteins (PubMed:17937914, PubMed:23891004). As a CIA complex component, interacts specifically with CIAO2A or CIAO2B and MMS19 to assist different branches of iron-sulfur protein assembly, depending of its interactors. The complex CIAO1:CIAO2B:MMS19 binds to and facilitates the assembly of most cytosolic-nuclear Fe/S proteins. CIAO1:CIAO2A specifically matures ACO1 and stabilizes IREB2 (PubMed:23891004). Seems to specifically modulate the transactivation activity of WT1 (PubMed:9556563). As part of the mitotic spindle-associated MMXD complex it may play a role in chromosome segregation (PubMed:20797633).

100 Clinical Results associated with CIAO1

100 Translational Medicine associated with CIAO1

0 Patents (Medical) associated with CIAO1

Literatures (Medical) associated with CIAO1

09 Sep 2024·Nucleic Acids Research

The critical role of the iron–sulfur cluster and CTC components in DOG-1/BRIP1 function in Caenorhabditis elegans

Article

Author: Rodrigues Alves Barbosa, Victoria ; Li, Xiao ; Diao, Catherine ; Perdomo, Ivette Maria Menendez ; Tarailo-Graovac, Maja

AbstractFANCJ/BRIP1, initially identified as DOG-1 (Deletions Of G-rich DNA) in Caenorhabditis elegans, plays a critical role in genome integrity by facilitating DNA interstrand cross-link repair and resolving G-quadruplex structures. Its function is tightly linked to a conserved [4Fe–4S] cluster-binding motif, mutations of which contribute to Fanconi anemia and various cancers. This study investigates the critical role of the iron–sulfur (Fe–S) cluster in DOG-1 and its relationship with the cytosolic iron–sulfur protein assembly targeting complex (CTC). We found that a DOG-1 mutant, expected to be defective in Fe–S cluster binding, is primarily localized in the cytoplasm, leading to heightened DNA damage sensitivity and G-rich DNA deletions. We further discovered that the deletion of mms-19, a nonessential CTC component, also resulted in DOG-1 sequestered in cytoplasm and increased DNA damage sensitivity. Additionally, we identified that CIAO-1 and CIAO-2B are vital for DOG-1’s stability and repair functions but unlike MMS-19 have essential roles in C. elegans. These findings confirm the CTC and Fe–S cluster as key elements in regulating DOG-1, crucial for genome integrity. Additionally, this study advances our understanding of the CTC’s role in Fe–S protein regulation and development in C. elegans, offering a model to study its impact on multicellular organism development.

17 Jun 2024·Journal of Clinical Investigation

CIAO1 loss of function causes a neuromuscular disorder with compromise of nucleocytoplasmic Fe-S enzymes

Article

Author: Straub, Volker ; Muntoni, Francesco ; Zaharieva, Irina T ; Pais, Lynn ; Silverstein, Sarah ; Sewry, Caroline ; Hu, Ying ; Sarkozy, Anna ; Orbach, Rotem ; Sudhakar, Sniya ; Verma, Sumit ; Peric, Stojan ; Willis, Tracey ; Mueller, Juliane ; DiTroia, Stephanie ; Donkervoort, Sandra ; Maio, Nunziata ; Bönnemann, Carsten G ; Foley, A Reghan ; Munot, Pinki ; Töpf, Ana ; Rouault, Tracey A ; Douglas, Ganka ; Grunseich, Christopher ; Krishnakumar, Deepa

Cytoplasmic and nuclear iron-sulfur (Fe-S) enzymes that are essential for genome maintenance and replication depend on the cytoplasmic Fe-S assembly (CIA) machinery for cluster acquisition. The core of the CIA machinery consists of a complex of CIAO1, MMS19 and FAM96B. The physiological consequences of loss of function in the components of the CIA pathway have thus far remained uncharacterized. Our study revealed that patients with biallelic loss of function in CIAO1 developed proximal and axial muscle weakness, fluctuating creatine kinase elevation, and respiratory insufficiency. In addition, they presented with CNS symptoms including learning difficulties and neurobehavioral comorbidities, along with iron deposition in deep brain nuclei, mild normocytic to macrocytic anemia, and gastrointestinal symptoms. Mutational analysis revealed reduced stability of the variants compared with WT CIAO1. Functional assays demonstrated failure of the variants identified in patients to recruit Fe-S recipient proteins, resulting in compromised activities of DNA helicases, polymerases, and repair enzymes that rely on the CIA complex to acquire their Fe-S cofactors. Lentivirus-mediated restoration of CIAO1 expression reversed all patient-derived cellular abnormalities. Our study identifies CIAO1 as a human disease gene and provides insights into the broader implications of the cytosolic Fe-S assembly pathway in human health and disease.

01 Jun 2024·Genetics in Medicine

CIAO1 and MMS19 deficiency: A lethal neurodegenerative phenotype caused by cytosolic Fe-S cluster protein assembly disorders

Author: van der Wel, Nicole N ; Moeschler, John B ; Ban, Kevin ; Grootemaat, Anita E ; Schomakers, Bauke V ; Leen, René ; Dobritzsch, Doreen ; Labrune, Philippe ; van Klinken, Jan B ; Roseboom, Winfried ; Filiano, James J ; Kochan, Jakub ; Dyment, David ; van Karnebeek, Clara D M ; Berman, Jason N ; van der Lee, Robin ; Ross, Colin J ; Pena, Izabella A ; Drögemöller, Britt I ; Kramer, Gertjan ; Correard, Solenne ; Pras-Raves, Mia L ; Jaspers, Yorrick R J ; Weschke, Bernhard ; Meinsma, Rutger ; Roelofsen, Jeroen ; McIntyre, Rebecca L ; Ferreira, Carlos R ; van Kuilenburg, André B P ; Tarailo-Graovac, Maja ; Zoetekouw, Lida ; Wasserman, Wyeth W ; Prykhozhij, Sergey V ; Garavaglia, Barbara ; Schock, Sarah ; Ekker, Marc ; van Weeghel, Michel ; Houtkooper, Riekelt H ; Riva, Daria ; Willemsen, Michèl A ; Saxena, Vishal ; Vaz, Frédéric M ; Jansen-Meijer, Judith

PURPOSEThe functionality of many cellular proteins depends on cofactors; yet, they have only been implicated in a minority of Mendelian diseases. Here, we describe the first 2 inherited disorders of the cytosolic iron-sulfur protein assembly system.METHODSGenetic testing via genome sequencing was applied to identify the underlying disease cause in 3 patients with microcephaly, congenital brain malformations, progressive developmental and neurologic impairments, recurrent infections, and a fatal outcome. Studies in patient-derived skin fibroblasts and zebrafish models were performed to investigate the biochemical and cellular consequences.RESULTSMetabolic analysis showed elevated uracil and thymine levels in body fluids but no pathogenic variants in DPYD, encoding dihydropyrimidine dehydrogenase. Genome sequencing identified compound heterozygosity in 2 patients for missense variants in CIAO1, encoding cytosolic iron-sulfur assembly component 1, and homozygosity for an in-frame 3-nucleotide deletion in MMS19, encoding the MMS19 homolog, cytosolic iron-sulfur assembly component, in the third patient. Profound alterations in the proteome, metabolome, and lipidome were observed in patient-derived fibroblasts. We confirmed the detrimental effect of deficiencies in CIAO1 and MMS19 in zebrafish models.CONCLUSIONA general failure of cytosolic and nuclear iron-sulfur protein maturation caused pleiotropic effects. The critical function of the cytosolic iron-sulfur protein assembly machinery for antiviral host defense may well explain the recurrent severe infections occurring in our patients.

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