Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0016226 iron-sulfur cluster assembly	IBA GO_REF:0000033	ACCEPT	Summary: CIAO1 is a core component of the CIA targeting complex that mediates Fe-S cluster transfer to cytosolic and nuclear client proteins. The IBA annotation from phylogenetic inference is strongly supported by multiple human studies demonstrating CIAO1's essential role in Fe-S protein maturation (PMID:23891004, PMID:22678361, PMID:22678362, PMID:38950322). Reason: This annotation correctly captures CIAO1's central role in the CIA pathway. Multiple primary studies confirm CIAO1 functions in iron-sulfur cluster assembly by facilitating cluster transfer to cytosolic-nuclear Fe-S proteins (PMID:23891004). Loss of CIAO1 results in compromised biogenesis of Fe-S enzymes like POLD1 and DPYD (PMID:38950322). Supporting Evidence: PMID:23891004 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 PMID:38950322 Functional assays revealed selective compromise of the biogenesis of Fe-S enzymes that are known clients of the CIA complex, namely dihydropyrimidine dehydrogenase (DPYD)
GO:0097361 cytosolic [4Fe-4S] assembly targeting complex	IBA GO_REF:0000033	ACCEPT	Summary: CIAO1 is a core structural component of the cytosolic [4Fe-4S] assembly targeting complex (CTC), together with MMS19 and CIAO2B/FAM96B. The IBA annotation is well-supported by multiple experimental studies (PMID:22678361, PMID:22678362, PMID:23585563, PMID:23891004). Reason: This cellular component annotation accurately reflects CIAO1's established role as a core subunit of the CTC. Multiple independent studies have demonstrated this complex membership through co-immunoprecipitation and size exclusion chromatography. Supporting Evidence: PMID:23585563 Here, we show that MMS19, MIP18, and CIAO1 form a tight "core" complex and that IOP1 is an "external" component of this complex PMID:23891004 CIA1 associates with either CIA2A or CIA2B and the CIA-targeting factor MMS19
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: CIAO1 is a cytoplasmic protein that functions in the late-acting CIA machinery. This is supported by subcellular fractionation studies (PMID:23585563) and consistent with its role in cytosolic Fe-S protein assembly. Reason: The cytoplasmic localization is well-established experimentally and consistent with CIAO1's role in the cytosolic iron-sulfur protein assembly pathway. This IEA annotation is accurate. Supporting Evidence: PMID:38950322 the 3 core components of the CIA complex, which specifically localizes to the cytosolic compartment of mammalian cells file:human/CIAO1/CIAO1-deep-research-falcon.md CIAO1 is cytosolic and functions in the late cytosolic/nuclear Fe-S assembly step
GO:0007059 chromosome segregation	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: CIAO1 is part of the MMXD complex (MMS19-MIP18-XPD) which localizes to the mitotic spindle during mitosis and is implicated in chromosome segregation (PMID:20797633). However, this appears to be a secondary role related to its function in maturing Fe-S proteins like XPD rather than a direct role in the segregation machinery. Reason: While CIAO1's involvement in chromosome segregation via the MMXD complex is documented (PMID:20797633), this is likely an indirect consequence of its role in maturing Fe-S cluster-containing proteins such as XPD that are required for proper chromosome segregation. The core function of CIAO1 is in Fe-S cluster assembly/transfer. Supporting Evidence: PMID:20797633 MMS19, MIP18, and XPD localized to the mitotic spindle during mitosis. The siRNA-mediated knockdown of MMS19, MIP18, or XPD led to improper chromosome segregation
GO:0016226 iron-sulfur cluster assembly	IEA GO_REF:0000120	ACCEPT	Summary: This IEA annotation based on automated methods correctly captures CIAO1's role in iron-sulfur cluster assembly, which is strongly supported by experimental evidence. Reason: This is a correct annotation that aligns with the experimentally verified function of CIAO1 in the CIA pathway. Supporting Evidence: PMID:23891004 CIA2B-CIA1-MMS19 and CIA2A-CIA1 assist different branches of Fe/S protein assembly
GO:0071817 MMXD complex	IEA GO_REF:0000104	ACCEPT	Summary: CIAO1 was identified as a component of the MMXD complex (MMS19-MIP18-XPD-Ciao1-ANT2) by Ito et al. 2010 (PMID:20797633). This complex functions independently of TFIIH and is involved in chromosome segregation. Reason: This annotation is supported by direct experimental evidence from PMID:20797633 demonstrating CIAO1's membership in the MMXD complex. Supporting Evidence: PMID:20797633 the MMS19-XPD complex did not contain any other subunits of TFIIH. Instead, it included FAM96B (now designated MIP18), Ciao1, and ANT2
GO:0097361 cytosolic [4Fe-4S] assembly targeting complex	IEA GO_REF:0000120	ACCEPT	Summary: This IEA annotation correctly reflects CIAO1's membership in the cytosolic [4Fe-4S] assembly targeting complex, supported by extensive experimental data. Reason: Accurate annotation consistent with multiple experimental studies demonstrating CIAO1 is a core component of the CTC.
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	MARK AS OVER ANNOTATED	Summary: High-throughput protein interaction study. Protein binding is too general and uninformative for CIAO1's specific role as a scaffold/adapter in Fe-S cluster transfer. Reason: The term 'protein binding' is non-informative for CIAO1 which has a specific scaffold function in the CIA targeting complex. The actual molecular function involves acting as a client docking platform for Fe-S protein maturation, which is not well captured by this generic term. Supporting Evidence: PMID:16189514 Towards a proteome-scale map of the human protein-protein interaction network.
GO:0005515 protein binding	IPI PMID:17353931 Large-scale mapping of human protein-protein interactions by...	MARK AS OVER ANNOTATED	Summary: Large-scale mass spectrometry protein interaction mapping. Shows interaction with MMS19 (Q96T76) but 'protein binding' is too general. Reason: While the interaction data is valid, 'protein binding' does not capture the functional significance of CIAO1's role as a scaffold in the CIA targeting complex. Supporting Evidence: PMID:17353931 Large-scale mapping of human protein-protein interactions by mass spectrometry.
GO:0005515 protein binding	IPI PMID:21516116 Next-generation sequencing to generate interactome datasets.	MARK AS OVER ANNOTATED	Summary: Next-generation sequencing interactome study showing interaction with MMS19 and CIAO2B (FAM96B). Generic protein binding annotation. Reason: The specific interactions are meaningful for understanding CIA complex assembly, but 'protein binding' is too vague to be informative. Supporting Evidence: PMID:21516116 Next-generation sequencing to generate interactome datasets.
GO:0005515 protein binding	IPI PMID:23585563 IOP1 protein is an external component of the human cytosolic...	MARK AS OVER ANNOTATED	Summary: This publication (Seki et al. 2013) demonstrates specific interactions between CIAO1 and ERCC2/XPD, CIAO3/IOP1, and CIAO2B within the CIA complex. These are functionally relevant interactions for Fe-S cluster delivery. Reason: The underlying data is valuable but 'protein binding' is too generic. The interactions represent CIAO1's role as a scaffold in the CIA targeting complex. Supporting Evidence: PMID:23585563 MIP18 has a role to bridge MMS19 and CIAO1. CIAO1 also binds IOP1
GO:0005515 protein binding	IPI PMID:24245804 Viperin is an iron-sulfur protein that inhibits genome synth...	MARK AS OVER ANNOTATED	Summary: Shows interaction with viperin (RSAD2), an Fe-S protein that is a CIA client. Viperin requires Fe-S cluster for its antiviral activity. Reason: The interaction with viperin represents CIAO1's client interaction function, but 'protein binding' is uninformative. Supporting Evidence: PMID:24245804 Viperin is an iron-sulfur protein that inhibits genome synthesis of tick-borne encephalitis virus via radical SAM domain activity.
GO:0005515 protein binding	IPI PMID:24981860 Human-chromatin-related protein interactions identify a deme...	MARK AS OVER ANNOTATED	Summary: Human chromatin-related protein interaction study showing interactions with MMS19, CIAO2A, and CIAO2B components of the CIA complex. Reason: Relevant interactions but generic protein binding term is uninformative. Supporting Evidence: PMID:24981860 2014 Jun 26. Human-chromatin-related protein interactions identify a demethylase complex required for chromosome segregation.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: Proteome-scale interactome study. Shows multiple interactions including with CIA complex components. Reason: High-throughput data; protein binding is too general for curation purposes. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network.
GO:0005515 protein binding	IPI PMID:28178521 The CIA Targeting Complex Is Highly Regulated and Provides T...	MARK AS OVER ANNOTATED	Summary: This focused study on the CIA targeting complex demonstrates CIAO1 interactions with ERCC2/XPD and MMS19, providing important mechanistic insights into client binding by the CTC. Reason: Valuable mechanistic data about CIA targeting complex, but 'protein binding' is too generic. The publication supports the complex membership annotations. Supporting Evidence: PMID:28178521 The CIA Targeting Complex Is Highly Regulated and Provides Two Distinct Binding Sites for Client Iron-Sulfur Proteins
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: Architecture of human interactome study showing interaction with MMS19. Reason: High-throughput interactome data; protein binding is uninformative. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks.
GO:0005515 protein binding	IPI PMID:32222833 CIAO3 protein forms a stable ternary complex with two key pl...	MARK AS OVER ANNOTATED	Summary: This study demonstrates formation of a stable ternary complex of CIAO3, CIAO1, and CIAO2A, with a [4Fe-4S] cluster. Important for understanding CIA machinery. Reason: Mechanistically important data, but 'protein binding' does not capture the specific scaffold function of CIAO1 in the CIA complex. Supporting Evidence: PMID:32222833 the formation of a stable, [4Fe-4S]-bound, complex, composed by CIAO3 and the hetero-CIA2A-CIAO1 complex
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Reference map of human binary protein interactome showing multiple CIAO1 interactions. Reason: High-throughput interactome data; protein binding is too general. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Dual proteome-scale network study showing cell-specific CIAO1 interactions. Reason: Large-scale interaction data; protein binding is uninformative. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: Multimodal cell maps study for structural and functional genomics. Reason: High-throughput data; protein binding is too general. Supporting Evidence: PMID:40205054 Apr 9. Multimodal cell maps as a foundation for structural and functional genomics.
GO:0051604 protein maturation	IGI PMID:17937914 Structure of the yeast WD40 domain protein Cia1, a component...	MODIFY	Summary: This study on yeast Cia1 structure demonstrates that human CIAO1 can functionally replace yeast Cia1 in supporting cytosolic Fe-S protein biogenesis. The protein maturation annotation refers to the maturation of Fe-S proteins through cluster insertion. Reason: While CIAO1 does participate in protein maturation (specifically of Fe-S proteins), a more precise annotation would be 'iron-sulfur cluster assembly' (GO:0016226) which is already present. The term 'protein maturation' is too general. Proposed replacements: iron-sulfur cluster assembly Supporting Evidence: PMID:17937914 We show that Ciao1 can functionally replace Cia1 and support cytosolic Fe/S protein biogenesis
GO:0051604 protein maturation	IMP PMID:23891004 Human CIA2A-FAM96A and CIA2B-FAM96B integrate iron homeostas...	MODIFY	Summary: This study demonstrates that CIAO1 facilitates assembly/maturation of cytosolic-nuclear Fe-S proteins by participating in cluster insertion. While technically protein maturation, the more specific term 'iron-sulfur cluster assembly' better captures the function. Reason: The specific function is iron-sulfur cluster insertion into apo-proteins, which is already captured by GO:0016226. 'Protein maturation' is overly broad. Proposed replacements: iron-sulfur cluster assembly Supporting Evidence: PMID:23891004 The CIA2B-CIA1-MMS19 complex binds to and facilitates assembly of most cytosolic-nuclear Fe/S proteins
GO:0097361 cytosolic [4Fe-4S] assembly targeting complex	IMP PMID:38950322 CIAO1 loss of function causes a neuromuscular disorder with ...	ACCEPT	Summary: This landmark 2024 study on CIAO1 loss-of-function patients demonstrates that CIAO1 is essential for CIA complex stability. Loss of CIAO1 leads to destabilization of MMS19 and FAM96B, confirming CIAO1's role as a core CTC component. Reason: Strong experimental evidence from patient-derived cells showing CIAO1 is essential for CTC stability and function. Supporting Evidence: PMID:38950322 CIAO1 protein levels were profoundly diminished in cytosolic lysates from P1-derived fibroblasts compared with parental cells (Figure 4, A and B, and Supplemental Figure 3, A and B), with a concomitant loss of the known CIAO1-interacting partners MMS19 and FAM96B (Figure 4A and Supplemental Figure 3, A and B)
GO:0005737 cytoplasm	NAS PMID:23585563 IOP1 protein is an external component of the human cytosolic...	ACCEPT	Summary: Cytoplasmic localization stated in the context of CIA complex characterization. Reason: Consistent with experimental data showing CIAO1 functions in the cytosol as part of the CIA machinery. Supporting Evidence: PMID:23585563 Epub 2013 Apr 12. IOP1 protein is an external component of the human cytosolic iron-sulfur cluster assembly (CIA) machinery and functions in the MMS19 protein-dependent CIA pathway.
GO:0016226 iron-sulfur cluster assembly	NAS PMID:23585563 IOP1 protein is an external component of the human cytosolic...	ACCEPT	Summary: CIAO1's role in iron-sulfur cluster assembly is discussed in the context of the CIA pathway. Reason: Accurate annotation supported by the publication's characterization of the CIA complex and CIAO1's role in Fe-S protein maturation. Supporting Evidence: PMID:23585563 Epub 2013 Apr 12. IOP1 protein is an external component of the human cytosolic iron-sulfur cluster assembly (CIA) machinery and functions in the MMS19 protein-dependent CIA pathway.
GO:0005737 cytoplasm	NAS PMID:32222833 CIAO3 protein forms a stable ternary complex with two key pl...	ACCEPT	Summary: Cytoplasmic localization in context of CIA complex studies. Reason: Consistent with established cytosolic function of CIAO1. Supporting Evidence: PMID:32222833 Epub 2020 Mar 28. CIAO3 protein forms a stable ternary complex with two key players of the human cytosolic iron-sulfur cluster assembly machinery.
GO:0016226 iron-sulfur cluster assembly	IDA PMID:32222833 CIAO3 protein forms a stable ternary complex with two key pl...	ACCEPT	Summary: This study demonstrates CIAO1 forms a stable ternary complex with CIAO3 and CIAO2A that is [4Fe-4S]-bound, directly supporting its role in iron-sulfur cluster assembly. Reason: Direct experimental evidence showing CIAO1's participation in Fe-S cluster containing complexes. Supporting Evidence: PMID:32222833 the formation of a stable, [4Fe-4S]-bound, complex, composed by CIAO3 and the hetero-CIA2A-CIAO1 complex
GO:0005737 cytoplasm	IDA PMID:23585563 IOP1 protein is an external component of the human cytosolic...	ACCEPT	Summary: Direct experimental evidence for cytoplasmic localization from subcellular fractionation studies. Reason: IDA evidence directly demonstrates cytoplasmic localization of CIAO1. Supporting Evidence: PMID:38950322 the 3 core components of the CIA complex, which specifically localizes to the cytosolic compartment of mammalian cells PMID:23585563 Epub 2013 Apr 12. IOP1 protein is an external component of the human cytosolic iron-sulfur cluster assembly (CIA) machinery and functions in the MMS19 protein-dependent CIA pathway.
GO:0097361 cytosolic [4Fe-4S] assembly targeting complex	IDA PMID:23585563 IOP1 protein is an external component of the human cytosolic...	ACCEPT	Summary: Direct demonstration of CIAO1 as a core component of the CTC through co-immunoprecipitation and biochemical studies. Reason: Strong experimental evidence showing CIAO1 is a core CTC component. Supporting Evidence: PMID:23585563 Here, we show that MMS19, MIP18, and CIAO1 form a tight "core" complex and that IOP1 is an "external" component of this complex
GO:0005515 protein binding	IPI PMID:23891004 Human CIA2A-FAM96A and CIA2B-FAM96B integrate iron homeostas...	MARK AS OVER ANNOTATED	Summary: This study demonstrates specific interactions between CIAO1 and multiple CIA components (CIAO2A, CIAO2B, MMS19) and client Fe-S proteins (ERCC2, POLD1, IREB2). Reason: The interactions are highly relevant for understanding CIA function, but 'protein binding' is too generic to be informative. The complex membership annotations better capture these functional relationships. Supporting Evidence: PMID:23891004 CIA1 associates with either CIA2A or CIA2B and the CIA-targeting factor MMS19
GO:0097361 cytosolic [4Fe-4S] assembly targeting complex	IDA PMID:23891004 Human CIA2A-FAM96A and CIA2B-FAM96B integrate iron homeostas...	ACCEPT	Summary: Comprehensive characterization of CIAO1 as a core component of the CTC, showing it forms distinct complexes with CIAO2A-CIAO1 and CIAO2B-CIAO1-MMS19. Reason: Key publication establishing CIAO1's role in the CIA targeting complex. Supporting Evidence: PMID:23891004 CIA2B-CIA1-MMS19 and CIA2A-CIA1 assist different branches of Fe/S protein assembly
GO:0097361 cytosolic [4Fe-4S] assembly targeting complex	IDA PMID:22678361 MMS19 links cytoplasmic iron-sulfur cluster assembly to DNA ...	ACCEPT	Summary: This Science paper demonstrates MMS19 forms a complex with CIAO1 and other CIA factors (IOP1/CIAO3, MIP18/CIAO2B) that links cytoplasmic Fe-S assembly to DNA metabolism. Reason: Landmark study establishing the CIA targeting complex. Supporting Evidence: PMID:22678361 MMS19 forms a complex with the cytoplasmic Fe-S assembly (CIA) proteins CIAO1, IOP1, and MIP18
GO:0097361 cytosolic [4Fe-4S] assembly targeting complex	IDA PMID:22678362 MMS19 assembles iron-sulfur proteins required for DNA metabo...	ACCEPT	Summary: Companion Science paper demonstrating MMS19 as part of the CIA targeting complex that facilitates Fe-S cluster insertion into DNA metabolism proteins. Reason: Foundational study for understanding the CTC and CIAO1's role in it. Supporting Evidence: PMID:22678362 MMS19 functions as part of the CIA targeting complex that specifically interacts with and facilitates iron-sulfur cluster insertion into apoproteins
GO:0071817 MMXD complex	IDA PMID:20797633 MMXD, a TFIIH-independent XPD-MMS19 protein complex involved...	ACCEPT	Summary: Direct identification of CIAO1 as a component of the MMXD complex (MMS19-MIP18-XPD-Ciao1-ANT2) through immunoprecipitation studies. Reason: Experimental evidence directly demonstrating CIAO1 is part of the MMXD complex. Supporting Evidence: PMID:20797633 the MMS19-XPD complex did not contain any other subunits of TFIIH. Instead, it included FAM96B (now designated MIP18), Ciao1, and ANT2
GO:0006357 regulation of transcription by RNA polymerase II	TAS PMID:9556563 Ciao 1 is a novel WD40 protein that interacts with the tumor...	KEEP AS NON CORE	Summary: The original 1998 CIAO1 paper identified it as a WT1-interacting protein that modulates WT1 transactivation activity. However, this was before CIAO1's primary role in Fe-S cluster assembly was understood. The effect on transcription is likely indirect through Fe-S protein maturation. Reason: While CIAO1 was originally identified as interacting with WT1 and modulating its transcriptional activity (PMID:9556563), this is now understood as a secondary/indirect effect. CIAO1's primary function is in the CIA pathway for Fe-S cluster assembly. The transcriptional effects may relate to Fe-S cluster-dependent transcription factors or chromatin modifiers. Supporting Evidence: PMID:9556563 Ciao 1 appears to specifically modulate the transactivation activity of WT1
GO:0140132 iron-sulfur cluster chaperone activity	NAS	NEW	Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:23891004 The CIA2B-CIA1-MMS19 complex binds to and facilitates assembly of most cytosolic-nuclear Fe/S proteins PMID:38950322 CIAO1 is a key component of the CIA machinery

Core Functions

CIAO1 is a core component of the cytosolic iron-sulfur assembly (CIA) targeting complex that facilitates transfer of [4Fe-4S] clusters to cytosolic and nuclear Fe-S proteins. Multiple independent studies confirm this role (PMID:22678361, PMID:22678362, PMID:23891004, PMID:23585563, PMID:38950322). Loss of CIAO1 results in compromised Fe-S protein maturation.

Molecular Function:

iron-sulfur cluster chaperone activity

Directly Involved In:

iron-sulfur cluster assembly

Cellular Locations:

cytoplasm

In Complex:

cytosolic [4Fe-4S] assembly targeting complex

Supporting Evidence:

PMID:23891004
The CIA2B-CIA1-MMS19 complex binds to and facilitates assembly of most cytosolic-nuclear Fe/S proteins
PMID:38950322
CIAO1 is a key component of the CIA machinery

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000104

Electronic Gene Ontology annotations created by transferring manual GO annotations between related proteins based on shared sequence features

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:16189514

Towards a proteome-scale map of the human protein-protein interaction network.

PMID:17353931

Large-scale mapping of human protein-protein interactions by mass spectrometry.

PMID:17937914

Structure of the yeast WD40 domain protein Cia1, a component acting late in iron-sulfur protein biogenesis.

Human CIAO1 can functionally replace yeast Cia1 in supporting cytosolic Fe-S protein biogenesis
Crystal structure of Cia1 reveals a 7-bladed beta-propeller WD40 domain

PMID:20797633

MMXD, a TFIIH-independent XPD-MMS19 protein complex involved in chromosome segregation.

CIAO1 is a component of the MMXD complex (MMS19-MIP18-XPD-CIAO1-ANT2)
MMXD localizes to the mitotic spindle during mitosis
Knockdown leads to improper chromosome segregation

PMID:21516116

Next-generation sequencing to generate interactome datasets.

PMID:22678361

MMS19 links cytoplasmic iron-sulfur cluster assembly to DNA metabolism.

MMS19 forms a complex with CIAO1, IOP1, and MIP18
This complex facilitates Fe-S cluster transfer to DNA metabolism proteins
MMS19 knockout is preimplantation lethal in mice

PMID:22678362

MMS19 assembles iron-sulfur proteins required for DNA metabolism and genomic integrity.

MMS19 is part of the CIA targeting complex
The complex facilitates Fe-S cluster insertion into proteins for DNA replication and repair

PMID:23585563

IOP1 protein is an external component of the human cytosolic iron-sulfur cluster assembly (CIA) machinery and functions in the MMS19 protein-dependent CIA pathway.

MMS19, MIP18, and CIAO1 form a tight core complex
IOP1/CIAO3 is an external component
CIAO1 binds IOP1

PMID:23891004

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

CIAO1 associates with either CIAO2A or CIAO2B
CIA2B-CIA1-MMS19 complex matures most cytosolic-nuclear Fe-S proteins
CIA2A-CIA1 specifically matures ACO1/IRP1 and stabilizes IRP2

PMID:24245804

Viperin is an iron-sulfur protein that inhibits genome synthesis of tick-borne encephalitis virus via radical SAM domain activity.

PMID:24981860

Human-chromatin-related protein interactions identify a demethylase complex required for chromosome segregation.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:28178521

The CIA Targeting Complex Is Highly Regulated and Provides Two Distinct Binding Sites for Client Iron-Sulfur Proteins.

CTC provides two distinct client binding sites
Complex is highly regulated

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:32222833

CIAO3 protein forms a stable ternary complex with two key players of the human cytosolic iron-sulfur cluster assembly machinery.

CIAO3, CIAO1, and CIAO2A form a stable [4Fe-4S]-bound ternary complex
C-terminal [4Fe-4S] cluster of CIAO3 has structural role

PMID:32296183

A reference map of the human binary protein interactome.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:38950322

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

Biallelic CIAO1 loss-of-function causes MMDS10 (MIM 620960)
Patients have proximal muscle weakness, respiratory insufficiency, learning difficulties
CIAO1 loss destabilizes MMS19 and FAM96B
Multiple nucleocytoplasmic Fe-S enzymes are compromised (POLD1, DPYD, etc.)
Lentiviral CIAO1 restoration rescues all cellular defects

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

PMID:9556563

Ciao 1 is a novel WD40 protein that interacts with the tumor suppressor protein WT1.

Original identification of CIAO1 as a WT1-interacting protein
CIAO1 modulates WT1 transactivation activity
Does not affect WT1 DNA binding or repression activity

file:human/CIAO1/CIAO1-deep-research-falcon.md

Deep research report on CIAO1 function

CIAO1 is a WD40/beta-propeller protein and core component of the late-acting CIA machinery
A conserved C-terminal tripeptide TCR motif encodes specificity for CIA client targeting
CIAO1 loss-of-function variants cause a neuromuscular disorder with selective compromise of nucleocytoplasmic Fe-S enzymes

📚 Additional Documentation

Deep Research Falcon

(CIAO1-deep-research-falcon.md)

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template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: CIAO1
gene_symbol: CIAO1
uniprot_accession: O76071
protein_description: 'RecName: Full=Probable cytosolic iron-sulfur protein assembly
protein CIAO1 {ECO:0000255|HAMAP-Rule:MF_03037}; AltName: Full=WD repeat-containing
protein 39 {ECO:0000255|HAMAP-Rule:MF_03037};'
gene_info: Name=CIAO1 {ECO:0000255|HAMAP-Rule:MF_03037}; Synonyms=CIA1 {ECO:0000303|PubMed:23891004},
WDR39;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the WD repeat CIA1 family. {ECO:0000255|HAMAP-
protein_domains: CIAO1/Cia1. (IPR028608); WD40/YVTN_repeat-like_dom_sf. (IPR015943);
WD40_repeat_CS. (IPR019775); WD40_repeat_dom_sf. (IPR036322); WD40_rpt. (IPR001680)
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: O76071
Protein Description: RecName: Full=Probable cytosolic iron-sulfur protein assembly protein CIAO1 {ECO:0000255|HAMAP-Rule:MF_03037}; AltName: Full=WD repeat-containing protein 39 {ECO:0000255|HAMAP-Rule:MF_03037};
Gene Information: Name=CIAO1 {ECO:0000255|HAMAP-Rule:MF_03037}; Synonyms=CIA1 {ECO:0000303|PubMed:23891004}, WDR39;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the WD repeat CIA1 family. {ECO:0000255|HAMAP-
Key Domains: CIAO1/Cia1. (IPR028608); WD40/YVTN_repeat-like_dom_sf. (IPR015943); WD40_repeat_CS. (IPR019775); WD40_repeat_dom_sf. (IPR036322); WD40_rpt. (IPR001680)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "CIAO1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'CIAO1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene CIAO1 (gene ID: CIAO1, UniProt: O76071) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: O76071
Protein Description: RecName: Full=Probable cytosolic iron-sulfur protein assembly protein CIAO1 {ECO:0000255|HAMAP-Rule:MF_03037}; AltName: Full=WD repeat-containing protein 39 {ECO:0000255|HAMAP-Rule:MF_03037};
Gene Information: Name=CIAO1 {ECO:0000255|HAMAP-Rule:MF_03037}; Synonyms=CIA1 {ECO:0000303|PubMed:23891004}, WDR39;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the WD repeat CIA1 family. {ECO:0000255|HAMAP-
Key Domains: CIAO1/Cia1. (IPR028608); WD40/YVTN_repeat-like_dom_sf. (IPR015943); WD40_repeat_CS. (IPR019775); WD40_repeat_dom_sf. (IPR036322); WD40_rpt. (IPR001680)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "CIAO1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene CIAO1 (gene ID: CIAO1, UniProt: O76071) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Comprehensive research report: Human CIAO1 (UniProt O76071)

Verification of target identity and domain architecture
- CIAO1 (also known as CIA1 or WDR39) is the human ortholog of yeast Cia1, a WD40/β‑propeller protein and core component of the late-acting cytosolic iron–sulfur (Fe–S) protein assembly system. Its role is established in the “CIA targeting complex” (CTC) with MMS19 and CIAO2 subunits (CIAO2B/FAM96B and paralog CIAO2A/FAM96A). Structural and biochemical reviews and primary studies consistently place CIAO1 as a WD40-domain scaffold for client docking within the CTC (ciofibaffoni2018proteinnetworksin pages 16-18, wietmarschen2012themammalianproteins pages 1-2).

Key concepts and definitions
- CIA pathway and late-acting targeting complex: In eukaryotes, cytosolic and nuclear Fe–S proteins are matured by the CIA pathway. A late-acting “CIA targeting complex” (CTC) comprising MMS19 (HEAT-repeat scaffold), CIAO1 (WD40/β‑propeller), and CIAO2B (with CIAO2A as a paralogous subunit) recognizes apo-clients and delivers mature [4Fe–4S] clusters (fan2022ironregulatedassemblyof pages 1-2, wietmarschen2012themammalianproteins pages 1-2). CIAO1 resides in the CTC, providing a client docking surface with CIAO2 subunits, while MMS19 organizes the complex and interfaces with specific clients such as XPD/ERCC2 (fan2022ironregulatedassemblyof pages 1-2, wietmarschen2012themammalianproteins pages 1-2).
- Upstream cytosolic factors and mitochondrial dependency: Cytosolic [4Fe–4S] assembly begins on the NUBP1–NUBP2 (Cfd1–Nbp35) scaffold, powered by electron transfer from CIAPIN1 (DRE2/anamorsin) and NDOR1 (TAH18). The late factor CIAO3/NARFL (Nar1/IOP1) bridges early assembly to the CTC and depends on its own Fe–S binding to incorporate into higher-order complexes (fan2022ironregulatedassemblyof pages 1-2, ciofibaffoni2018proteinnetworksin pages 16-18). Mitochondrial ISC biogenesis is required upstream, exporting an ISC-derived sulfur compound via ABCB7 that supports cytosolic [4Fe–4S] assembly (fan2022ironregulatedassemblyof pages 1-2, wietmarschen2012themammalianproteins pages 1-2).

Recent developments and latest research (prioritize 2023–2024)
- Client recognition code unveiled (PNAS 2023): A conserved C-terminal tripeptide “TCR” motif, defined approximately as [L/I/M]-[D/E/S]-[W/F]-COO–, was shown to be necessary and sufficient to target clients to the CIA machinery. The CTC identifies more than thirty clients, and this motif encodes specificity for a substantial subset. The motif can be appended to nonnative proteins to recruit the CIA system for Fe–S delivery, revealing a generalizable recognition code (https://doi.org/10.1073/pnas.2311057120, Oct 2023) (marquez2023cytosoliciron–sulfurprotein pages 1-2).
- Quantitative prevalence of the TCR motif: Marquez et al. 2023 report that a substantial fraction of clients use the C-terminal tripeptide code; their summary indicates more than a quarter of CIA clients or adaptors carry the motif. Independent follow-up work reports ~20–25% motif prevalence and maps the docking to the CIAO1–CIAO2 interface; although these 2025 data are preprint-stage, they align with the 2023 PNAS study (https://doi.org/10.1101/2025.03.25.645274, Mar 2025) (marquez2023cytosoliciron–sulfurprotein pages 1-2, buzuk2025thecia1and pages 1-3).
- Mechanistic docking and binding site on CIAO1–CIAO2: Biophysical analyses indicate the TCR motif binds a conserved pocket at the CIAO1–CIAO2 interface, with hot-spot arginines contributed by both subunits. Neither subunit binds efficiently alone, supporting recognition by the assembled CTC. Pathogenic human CIAO1 variants (e.g., R65W) weaken CIAO2A binding and TCR affinity, linking the recognition interface to disease (https://doi.org/10.1101/2025.03.25.645274, Mar 2025) (buzuk2025thecia1and pages 6-8, buzuk2025thecia1and pages 8-11, buzuk2025thecia1and pages 11-13).
- Iron- and complex-state regulation (JBC 2022): Quantitative proteomics defined iron-dependent assembly of CIA components, showing CTCs of ~400–1000 kDa that engage CIAO3/NARFL and scaffold NUBP1/2; CIAO3 incorporation depends on its Fe–S cofactor. The work cataloged CIA substrates and linked CIA dynamics to cellular iron and redox status (https://doi.org/10.1016/j.jbc.2022.102094, Jul 2022) (fan2022ironregulatedassemblyof pages 1-2).
- CIAO1-related human genetics (2023–2024): Biallelic CIAO1 loss-of-function (LoF) variants cause a neuromuscular disorder with multi-system involvement and selective compromise of nucleocytoplasmic Fe–S enzymes; restoration of CIAO1 rescues cellular defects (https://doi.org/10.1101/2023.12.20.23300170, Dec 2023) (maio2023lossoffunction pages 1-5, maio2023lossoffunction pages 15-18). Complementary clinical genetics in 2024 implicate deficiency of CIAO1/MMS19 in a lethal neurodegenerative phenotype, underscoring essentiality of the late CIA targeting step (Genetics in Medicine 2024; see also mechanistic context in JBC 2022) (fan2022ironregulatedassemblyof pages 1-2).

Mechanistic function and pathway position of CIAO1
- Role in delivery and client selection: CIAO1 participates in client selection within the CTC by forming a composite binding surface with CIAO2B (or CIAO2A) that recognizes the TCR motif; MMS19 provides additional scaffolding and client engagement surfaces. Upstream, CIAO3/NARFL associates with the CTC to deliver the [4Fe–4S] cluster assembled on NUBP1/2, completing maturation of cytosolic and nuclear enzymes (fan2022ironregulatedassemblyof pages 1-2, marquez2023cytosoliciron–sulfurprotein pages 1-2). The CIA machinery collectively services >30 clients, including enzymes in DNA replication/repair (XPD/ERCC2, DNA polymerases), translation (ABCE1), and metabolism (DPYD, CDKAL1) (fan2022ironregulatedassemblyof pages 1-2, wietmarschen2012themammalianproteins pages 1-2).
- Quantitative aspects of recognition: The PNAS 2023 study establishes the TCR motif as a portable targeting signal for CIA delivery and indicates that a sizable proportion (reported as more than a quarter) of clients/adaptors terminate in such a motif, while others likely use distinct recognition surfaces on MMS19/CIAO1/CIAO2 or adaptor proteins (marquez2023cytosoliciron–sulfurprotein pages 1-2). Independent biochemical measurements (preprint) report micromolar binding affinities for minimal TCR peptides to assembled CIAO1–CIAO2 complexes and identify conserved arginine residues essential for recognition (buzuk2025thecia1and pages 6-8, buzuk2025thecia1and pages 8-11, buzuk2025thecia1and pages 11-13).

Subcellular localization and cellular compartmentation
- CIAO1 is cytosolic and functions in the late cytosolic/nuclear Fe–S assembly step. While its activity occurs in the cytosol, the matured clients include many nuclear enzymes; thus CIAO1 indirectly supports nuclear processes. Yeast Cia1 shows predominant nuclear localization, and human CIAO1 has been proposed to influence transcriptional processes via client maturation, consistent with its impact on DNA metabolic enzymes (frigerio2025controlofreplication pages 9-10).

Current applications and real-world implementations
- Diagnostic genetics and functional assays: CIAO1 LoF variants define a neuromuscular disorder with distinctive biochemical signatures—specific loss of nucleocytoplasmic Fe–S enzyme activities with preserved cytosolic IRP1/ACO1 activity—supporting targeted biochemical assessment of the CIA pathway in patient-derived cells. Rescue by CIAO1 re-expression suggests a path for functional confirmation of variants of uncertain significance (https://doi.org/10.1101/2023.12.20.23300170, Dec 2023) (maio2023lossoffunction pages 15-18).
- Engineering Fe–S delivery: The TCR motif discovery enables synthetic recruitment of the CIA machinery to nonnative proteins, facilitating Fe–S cofactor insertion for biotechnological applications where metallation in the cytosol is limiting (https://doi.org/10.1073/pnas.2311057120, Oct 2023) (marquez2023cytosoliciron–sulfurprotein pages 1-2).

Expert opinions and analyses from authoritative sources
- Reviews in 2018–2024 emphasize the centrality of CIAO1 within the CTC and the dependency of cytosolic/nuclear Fe–S biogenesis on mitochondrial ISC export. CIAO1, together with CIAO2B and MMS19, provides the docking platform required for accurate client selection and Fe–S insertion. Disruption of this module yields genome instability via compromised Fe–S–dependent DNA metabolic enzymes (ciofibaffoni2018proteinnetworksin pages 16-18, wietmarschen2012themammalianproteins pages 1-2, fan2022ironregulatedassemblyof pages 1-2). Recent overviews of replication stress and genome maintenance further underscore the CIA machinery’s role in safeguarding DNA replication and repair, mediated in part by CIAO1-containing complexes (frigerio2025controlofreplication pages 10-12).

Relevant statistics and quantitative data (recent studies)
- CIA client count and motif prevalence: The eukaryotic CIA system services more than 30 known cytosolic/nuclear Fe–S clients. Among these, the fraction terminating in a CTC recognition tripeptide was reported as more than a quarter in 2023 PNAS, with independent estimates around 20–25% in subsequent analyses; motif sufficiency was demonstrated by gain-of-function targeting experiments (https://doi.org/10.1073/pnas.2311057120, Oct 2023; https://doi.org/10.1101/2025.03.25.645274, Mar 2025) (marquez2023cytosoliciron–sulfurprotein pages 1-2, buzuk2025thecia1and pages 1-3).
- Complex size and assembly dependency: Human CTCs form large assemblies (~400–1000 kDa) whose organization depends on iron status and the Fe–S state of CIAO3/NARFL; ABCB7-dependent export from mitochondria supplies the cytosolic [4Fe–4S] assembly on NUBP1/2 (https://doi.org/10.1016/j.jbc.2022.102094, Jul 2022) (fan2022ironregulatedassemblyof pages 1-2).
- Disease-linked quantitative phenotypes: Patient-derived cells with CIAO1 LoF show markedly reduced CIAO1 protein levels, destabilization of MMS19 and CIAO2B, and decreased levels/activity of multiple nucleocytoplasmic Fe–S enzymes, while non-CIA cytosolic IRP1 activity remains intact—providing a quantitative biochemical signature of late CIA failure (https://doi.org/10.1101/2023.12.20.23300170, Dec 2023) (maio2023lossoffunction pages 15-18).

Cancer and genome integrity links
- The CIA machinery supports genome integrity through Fe–S–dependent DNA replication and repair enzymes. Reviews highlight that disruption of CIAO1-containing complexes destabilizes DNA polymerases and helicases (e.g., XPD/ERCC2), sensitizing cells to replication stress and promoting genome instability, processes relevant to cancer biology (wietmarschen2012themammalianproteins pages 1-2, frigerio2025controlofreplication pages 10-12). Iron- and oxygen-responsive regulation of CIA complex assembly suggests environmental modulation of genome maintenance capacity (fan2022ironregulatedassemblyof pages 1-2).

Open questions and future directions
- The balance of TCR-dependent versus TCR-independent client recognition, the structural basis of Fe–S delivery transition from CIAO3/NARFL to the CTC, and the full repertoire of adaptors remain active research areas. Isolation of fully holo (Fe–S–loaded) CTCs remains challenging, and how cluster occupancy affects client binding is unresolved (buzuk2025thecia1and pages 11-13, fan2022ironregulatedassemblyof pages 1-2).

Complex membership, partners, roles, and localization (quick reference)
| Component/Complex | Human gene/protein names (aliases) | Primary role in CIA | Direct partners | Subcellular localization | Key 2012–2024 evidence (context IDs) |
|---|---|---|---|---|---|
| CIA targeting complex (CTC) | MMS19–CIAO1–CIAO2B (FAM96B); CIAO2A (FAM96A)–CIAO1 subcomplex | Late-acting targeting/delivery of [4Fe–4S] to cytosolic/nuclear clients; client recognition | MMS19, CIAO1, CIAO2B/CIAO2A; binds CIAO3/NARFL; interfaces with clients | Cytosol; services nuclear clients | (fan2022ironregulatedassemblyof pages 1-2, marquez2023cytosoliciron–sulfurprotein pages 1-2, wietmarschen2012themammalianproteins pages 1-2, frigerio2025controlofreplication pages 9-10) |
| CIAO1 (Cia1 homolog) | CIAO1 (WDR39; CIA1) | WD40/β‑propeller scaffold; client docking; part of CTC | Binds CIAO2A/B; associates with MMS19 within CTC; engages clients | Cytosol; functions impact nucleus via client maturation | (ciofibaffoni2018proteinnetworksin pages 16-18, wietmarschen2012themammalianproteins pages 1-2, fan2022ironregulatedassemblyof pages 1-2) |
| CIAO2B (FAM96B) / CIAO2A (FAM96A) | FAM96B; FAM96A | CIAO2B: general CTC subunit; CIAO2A: subset-specific (e.g., IRP1) targeting; potential TCR binding | Bind CIAO1; tether MMS19; interact with NARFL/IOP1 | Cytosol | (ciofibaffoni2018proteinnetworksin pages 16-18, fan2022ironregulatedassemblyof pages 1-2) |
| MMS19 (Met18 homolog) | MMS19 | HEAT‑repeat scaffold in CTC; recruits/positions clients; regulated oligomerization | CIAO1, CIAO2B; clients (e.g., XPD/ERCC2) | Cytosol; supports nuclear enzyme maturation | (wietmarschen2012themammalianproteins pages 1-2, fan2022ironregulatedassemblyof pages 1-2) |
| CIAO3 / NARFL (Nar1/IOP1) | NARFL (IOP1) | Late carrier/adapter that bridges early scaffold to CTC; proposed to donate [4Fe–4S] | Interacts with CTC (MMS19–CIAO1–CIAO2B); NUBP1/2 | Cytosol | (fan2022ironregulatedassemblyof pages 1-2, ciofibaffoni2018proteinnetworksin pages 16-18, wietmarschen2012themammalianproteins pages 1-2) |
| Early cytosolic scaffold | NUBP1–NUBP2 (Cfd1–Nbp35) | Assembles [4Fe–4S] clusters de novo for cytosol | CIAPIN1 (DRE2) – NDOR1 (TAH18); NARFL | Cytosol | (fan2022ironregulatedassemblyof pages 1-2, ciofibaffoni2018proteinnetworksin pages 16-18) |
| Electron transfer to early scaffold | CIAPIN1 (DRE2/Anamorsin), NDOR1 (TAH18) | Delivers electrons to drive [4Fe–4S] assembly on NUBP1/2 | Interact with NUBP1/2; link to NARFL/CTC | Cytosol | (ciofibaffoni2018proteinnetworksin pages 16-18, wietmarschen2012themammalianproteins pages 1-2) |
| Mitochondrial ISC export | ABCB7 (mitochondrial exporter) | Exports ISC-derived sulfur compound essential for cytosolic [4Fe–4S] assembly | Upstream of NUBP1/2 | Mitochondria → cytosol | (fan2022ironregulatedassemblyof pages 1-2) |
| Disease involvement | CIAO1; MMS19 | Biallelic CIAO1 LoF neuromuscular disorder; CIAO1/MMS19 deficiency lethal neurodegeneration | Loss destabilizes CTC and compromises nucleocytoplasmic Fe–S enzymes | Tissues affected: muscle, CNS | (maio2023lossoffunction pages 1-5, maio2023lossoffunction pages 15-18, fan2022ironregulatedassemblyof pages 1-2) |

Table: Summary table of human CIAO1 (O76071) complexes, partners, roles, localization, and key evidence (2012–2024) useful for functional annotation and pathway mapping.

Notes on symbol disambiguation
- The evidence above consistently refers to human CIAO1 (O76071) as the Cia1 family WD40/β‑propeller subunit in the CIA targeting complex. Where yeast proteins are cited (Cia1, Cia2, Met18), they denote orthologs used to infer conserved mechanisms. No conflicting gene symbol usage was found within this scope.

Citations with URLs and dates
- Marquez MD et al. Cytosolic iron–sulfur protein assembly system identifies clients by a C-terminal tripeptide. PNAS. Oct 2023. https://doi.org/10.1073/pnas.2311057120 (marquez2023cytosoliciron–sulfurprotein pages 1-2)
- Fan X et al. Iron-regulated assembly of the cytosolic iron–sulfur cluster biogenesis machinery. J Biol Chem. Jul 2022. https://doi.org/10.1016/j.jbc.2022.102094 (fan2022ironregulatedassemblyof pages 1-2)
- van Wietmarschen N et al. The Mammalian Proteins MMS19, MIP18, and ANT2 Are Involved in Cytoplasmic Iron-Sulfur Cluster Protein Assembly. J Biol Chem. Dec 2012. https://doi.org/10.1074/jbc.m112.431270 (wietmarschen2012themammalianproteins pages 1-2)
- Ciofi-Baffoni S, Nasta V, Banci L. Protein networks in the maturation of human iron-sulfur proteins. Metallomics. Jan 2018. https://doi.org/10.1039/c7mt00269f (ciofibaffoni2018proteinnetworksin pages 16-18)
- Maio N et al. Loss of Function of the Cytoplasmic Fe-S Assembly Protein CIAO1 Causes a Neuromuscular Disorder with Compromise of Nucleocytoplasmic Fe-S Enzymes. medRxiv. Dec 2023. https://doi.org/10.1101/2023.12.20.23300170 (maio2023lossoffunction pages 1-5, maio2023lossoffunction pages 15-18)
- Frigerio C et al. Control of Replication Stress Response by Cytosolic Fe-S Cluster Assembly (CIA) Machinery. Cells. Mar 2025. https://doi.org/10.3390/cells14060442 (frigerio2025controlofreplication pages 10-12)
- Buzuk A et al. The Cia1 and Cia2 subunits of the CTC mediate recognition of apo-FeS proteins with a C-terminal targeting complex recognition motif. bioRxiv. Mar 2025. https://doi.org/10.1101/2025.03.25.645274 (preprint) (buzuk2025thecia1and pages 1-3, buzuk2025thecia1and pages 6-8, buzuk2025thecia1and pages 8-11, buzuk2025thecia1and pages 11-13)

Overall conclusion
CIAO1 (O76071) is a human WD40/β‑propeller protein that functions as a core subunit of the CIA targeting complex, partnering with MMS19 and CIAO2A/B to recognize apo-clients and insert [4Fe–4S] clusters assembled by the cytosolic scaffold with mitochondrial support. A 2023 breakthrough identified a conserved C-terminal tripeptide that encodes recognition for a substantial subset of clients and can be used to engineer Fe–S delivery. Human CIAO1 loss-of-function causes a neuromuscular disorder with selective compromise of nucleocytoplasmic Fe–S enzymes, linking CIAO1 to genome maintenance and disease. Regulation by iron and complex assembly state suggests broader physiological modulation of CIAO1 activity. These advances consolidate CIAO1’s central role in cytosolic/nuclear Fe–S biogenesis and inform diagnostics and bioengineering applications (marquez2023cytosoliciron–sulfurprotein pages 1-2, fan2022ironregulatedassemblyof pages 1-2, wietmarschen2012themammalianproteins pages 1-2, ciofibaffoni2018proteinnetworksin pages 16-18, maio2023lossoffunction pages 1-5, maio2023lossoffunction pages 15-18, frigerio2025controlofreplication pages 10-12, buzuk2025thecia1and pages 1-3, buzuk2025thecia1and pages 6-8, buzuk2025thecia1and pages 8-11, buzuk2025thecia1and pages 11-13).

References

(ciofibaffoni2018proteinnetworksin pages 16-18): Simone Ciofi-Baffoni, Veronica Nasta, and Lucia Banci. Protein networks in the maturation of human iron-sulfur proteins. Metallomics : integrated biometal science, 10 1:49-72, Jan 2018. URL: https://doi.org/10.1039/c7mt00269f, doi:10.1039/c7mt00269f. This article has 120 citations.
(wietmarschen2012themammalianproteins pages 1-2): Niek van Wietmarschen, Annie Moradian, Gregg B. Morin, Peter M. Lansdorp, and Evert-Jan Uringa. The mammalian proteins mms19, mip18, and ant2 are involved in cytoplasmic iron-sulfur cluster protein assembly. Journal of Biological Chemistry, 287:43351-43358, Dec 2012. URL: https://doi.org/10.1074/jbc.m112.431270, doi:10.1074/jbc.m112.431270. This article has 73 citations and is from a domain leading peer-reviewed journal.
(fan2022ironregulatedassemblyof pages 1-2): Xiaorui Fan, William D. Barshop, Ajay A. Vashisht, Vijaya Pandey, Stephanie Leal, Shima Rayatpisheh, Yasaman Jami-Alahmadi, Jihui Sha, and James A. Wohlschlegel. Iron-regulated assembly of the cytosolic iron–sulfur cluster biogenesis machinery. Journal of Biological Chemistry, 298:102094, Jul 2022. URL: https://doi.org/10.1016/j.jbc.2022.102094, doi:10.1016/j.jbc.2022.102094. This article has 24 citations and is from a domain leading peer-reviewed journal.
(marquez2023cytosoliciron–sulfurprotein pages 1-2): Melissa D. Marquez, Carina Greth, Anastasiya Buzuk, Yaxi Liu, Catharina M. Blinn, Simone Beller, Laura Leiskau, Anthony Hushka, Kassandra Wu, Kübra Nur, Daili J. A. Netz, Deborah L. Perlstein, and Antonio J. Pierik. Cytosolic iron–sulfur protein assembly system identifies clients by a c-terminal tripeptide. Proceedings of the National Academy of Sciences of the United States of America, Oct 2023. URL: https://doi.org/10.1073/pnas.2311057120, doi:10.1073/pnas.2311057120. This article has 23 citations and is from a highest quality peer-reviewed journal.
(buzuk2025thecia1and pages 1-3): A. Buzuk, Melissa D Marquez, JV Ho, Y. Liu, B. Wang, CC Qi, and DL Perlstein. The cia1 and cia2 subunits of the ctc mediate recognition of apo-fes proteins with a c-terminal targeting complex recognition motif. bioRxiv, Mar 2025. URL: https://doi.org/10.1101/2025.03.25.645274, doi:10.1101/2025.03.25.645274. This article has 1 citations and is from a poor quality or predatory journal.
(buzuk2025thecia1and pages 6-8): A. Buzuk, Melissa D Marquez, JV Ho, Y. Liu, B. Wang, CC Qi, and DL Perlstein. The cia1 and cia2 subunits of the ctc mediate recognition of apo-fes proteins with a c-terminal targeting complex recognition motif. bioRxiv, Mar 2025. URL: https://doi.org/10.1101/2025.03.25.645274, doi:10.1101/2025.03.25.645274. This article has 1 citations and is from a poor quality or predatory journal.
(buzuk2025thecia1and pages 8-11): A. Buzuk, Melissa D Marquez, JV Ho, Y. Liu, B. Wang, CC Qi, and DL Perlstein. The cia1 and cia2 subunits of the ctc mediate recognition of apo-fes proteins with a c-terminal targeting complex recognition motif. bioRxiv, Mar 2025. URL: https://doi.org/10.1101/2025.03.25.645274, doi:10.1101/2025.03.25.645274. This article has 1 citations and is from a poor quality or predatory journal.
(buzuk2025thecia1and pages 11-13): A. Buzuk, Melissa D Marquez, JV Ho, Y. Liu, B. Wang, CC Qi, and DL Perlstein. The cia1 and cia2 subunits of the ctc mediate recognition of apo-fes proteins with a c-terminal targeting complex recognition motif. bioRxiv, Mar 2025. URL: https://doi.org/10.1101/2025.03.25.645274, doi:10.1101/2025.03.25.645274. This article has 1 citations and is from a poor quality or predatory journal.
(maio2023lossoffunction pages 1-5): Nunziata Maio, Rotem Orbach, Irina Zaharieva, Ana Töpf, Sandra Donkervoort, Pinki Munot, Juliane Mueller, Tracey Willis, Sumit Verma, Stojan Peric, Deepa Krishnakumar, Sniya Sudhakar, Aileen Reghan Foley, Sarah Silverstein, Ganka Douglas, Lynn Pais, Stephanie DiTroia, Christopher Grunseich, Ying Hu, Caroline Sewry, Anna Sarkozy, Volker Straub, Francesco Muntoni, Tracey Rouault, and Carsten Gerhart Bönnemann. Loss of function of the cytoplasmic fe-s assembly protein ciao1 causes a neuromuscular disorder with compromise of nucleocytoplasmic fe-s enzymes. medRxiv : the preprint server for health sciences, Dec 2023. URL: https://doi.org/10.1101/2023.12.20.23300170, doi:10.1101/2023.12.20.23300170. This article has 4 citations.
(maio2023lossoffunction pages 15-18): Nunziata Maio, Rotem Orbach, Irina Zaharieva, Ana Töpf, Sandra Donkervoort, Pinki Munot, Juliane Mueller, Tracey Willis, Sumit Verma, Stojan Peric, Deepa Krishnakumar, Sniya Sudhakar, Aileen Reghan Foley, Sarah Silverstein, Ganka Douglas, Lynn Pais, Stephanie DiTroia, Christopher Grunseich, Ying Hu, Caroline Sewry, Anna Sarkozy, Volker Straub, Francesco Muntoni, Tracey Rouault, and Carsten Gerhart Bönnemann. Loss of function of the cytoplasmic fe-s assembly protein ciao1 causes a neuromuscular disorder with compromise of nucleocytoplasmic fe-s enzymes. medRxiv : the preprint server for health sciences, Dec 2023. URL: https://doi.org/10.1101/2023.12.20.23300170, doi:10.1101/2023.12.20.23300170. This article has 4 citations.
(frigerio2025controlofreplication pages 9-10): Chiara Frigerio, Michela Galli, Sara Castelli, Aurora Da Prada, and Michela Clerici. Control of replication stress response by cytosolic fe-s cluster assembly (cia) machinery. Cells, 14:442, Mar 2025. URL: https://doi.org/10.3390/cells14060442, doi:10.3390/cells14060442. This article has 3 citations and is from a poor quality or predatory journal.
(frigerio2025controlofreplication pages 10-12): Chiara Frigerio, Michela Galli, Sara Castelli, Aurora Da Prada, and Michela Clerici. Control of replication stress response by cytosolic fe-s cluster assembly (cia) machinery. Cells, 14:442, Mar 2025. URL: https://doi.org/10.3390/cells14060442, doi:10.3390/cells14060442. This article has 3 citations and is from a poor quality or predatory journal.

Citations

fan2022ironregulatedassemblyof pages 1-2
frigerio2025controlofreplication pages 9-10
maio2023lossoffunction pages 15-18
frigerio2025controlofreplication pages 10-12
wietmarschen2012themammalianproteins pages 1-2
ciofibaffoni2018proteinnetworksin pages 16-18
maio2023lossoffunction pages 1-5
4Fe–4S
L/I/M
D/E/S
W/F
https://doi.org/10.1073/pnas.2311057120,
https://doi.org/10.1101/2025.03.25.645274,
https://doi.org/10.1016/j.jbc.2022.102094,
https://doi.org/10.1101/2023.12.20.23300170,
https://doi.org/10.1073/pnas.2311057120
https://doi.org/10.1016/j.jbc.2022.102094
https://doi.org/10.1074/jbc.m112.431270
https://doi.org/10.1039/c7mt00269f
https://doi.org/10.1101/2023.12.20.23300170
https://doi.org/10.3390/cells14060442
https://doi.org/10.1101/2025.03.25.645274
https://doi.org/10.1039/c7mt00269f,
https://doi.org/10.1074/jbc.m112.431270,
https://doi.org/10.3390/cells14060442,

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id: O76071
gene_symbol: CIAO1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: CIAO1 (Cytosolic Iron-sulfur Assembly protein 1) is a WD40-repeat 
  beta-propeller protein that serves as a core component of the cytosolic 
  iron-sulfur (CIA) targeting complex (CTC). CIAO1 functions together with MMS19
  and CIAO2B (FAM96B) to form the late-acting CIA machinery that recognizes 
  apo-client proteins and facilitates the transfer of [4Fe-4S] clusters to 
  cytosolic and nuclear Fe-S proteins. CIAO1 also forms an alternative complex 
  with CIAO2A (FAM96A) that specifically matures cytosolic aconitase/IRP1 and 
  stabilizes IRP2 for iron homeostasis regulation. The CIAO1-CIAO2 interface 
  provides a client recognition surface that binds a C-terminal tripeptide motif
  (TCR motif) present on a substantial subset of CIA clients. Key clients of the
  CIA machinery include DNA replication and repair enzymes (POLD1, XPD/ERCC2, 
  RTEL1), translation machinery (ABCE1), and metabolic enzymes (DPYD). Biallelic
  loss-of-function variants in CIAO1 cause Multiple mitochondrial dysfunctions 
  syndrome 10 (MMDS10), a neuromuscular disorder characterized by proximal 
  muscle weakness, respiratory insufficiency, learning difficulties, and 
  compromised activities of nucleocytoplasmic Fe-S enzymes.
existing_annotations:
- term:
    id: GO:0016226
    label: iron-sulfur cluster assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: CIAO1 is a core component of the CIA targeting complex that 
      mediates Fe-S cluster transfer to cytosolic and nuclear client proteins. 
      The IBA annotation from phylogenetic inference is strongly supported by 
      multiple human studies demonstrating CIAO1's essential role in Fe-S 
      protein maturation (PMID:23891004, PMID:22678361, PMID:22678362, 
      PMID:38950322).
    action: ACCEPT
    reason: This annotation correctly captures CIAO1's central role in the CIA 
      pathway. Multiple primary studies confirm CIAO1 functions in iron-sulfur 
      cluster assembly by facilitating cluster transfer to cytosolic-nuclear 
      Fe-S proteins (PMID:23891004). Loss of CIAO1 results in compromised 
      biogenesis of Fe-S enzymes like POLD1 and DPYD (PMID:38950322).
    supported_by:
    - reference_id: PMID:23891004
      supporting_text: 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
    - reference_id: PMID:38950322
      supporting_text: Functional assays revealed selective compromise of the 
        biogenesis of Fe-S enzymes that are known clients of the CIA complex, 
        namely dihydropyrimidine dehydrogenase (DPYD)
- term:
    id: GO:0097361
    label: cytosolic [4Fe-4S] assembly targeting complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: CIAO1 is a core structural component of the cytosolic [4Fe-4S] 
      assembly targeting complex (CTC), together with MMS19 and CIAO2B/FAM96B. 
      The IBA annotation is well-supported by multiple experimental studies 
      (PMID:22678361, PMID:22678362, PMID:23585563, PMID:23891004).
    action: ACCEPT
    reason: This cellular component annotation accurately reflects CIAO1's 
      established role as a core subunit of the CTC. Multiple independent 
      studies have demonstrated this complex membership through 
      co-immunoprecipitation and size exclusion chromatography.
    supported_by:
    - reference_id: PMID:23585563
      supporting_text: Here, we show that MMS19, MIP18, and CIAO1 form a tight 
        "core" complex and that IOP1 is an "external" component of this complex
    - reference_id: PMID:23891004
      supporting_text: CIA1 associates with either CIA2A or CIA2B and the 
        CIA-targeting factor MMS19
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: CIAO1 is a cytoplasmic protein that functions in the late-acting 
      CIA machinery. This is supported by subcellular fractionation studies 
      (PMID:23585563) and consistent with its role in cytosolic Fe-S protein 
      assembly.
    action: ACCEPT
    reason: The cytoplasmic localization is well-established experimentally and 
      consistent with CIAO1's role in the cytosolic iron-sulfur protein assembly
      pathway. This IEA annotation is accurate.
    supported_by:
    - reference_id: PMID:38950322
      supporting_text: the 3 core components of the CIA complex, which 
        specifically localizes to the cytosolic compartment of mammalian cells
    - reference_id: file:human/CIAO1/CIAO1-deep-research-falcon.md
      supporting_text: CIAO1 is cytosolic and functions in the late 
        cytosolic/nuclear Fe-S assembly step
- term:
    id: GO:0007059
    label: chromosome segregation
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: CIAO1 is part of the MMXD complex (MMS19-MIP18-XPD) which localizes
      to the mitotic spindle during mitosis and is implicated in chromosome 
      segregation (PMID:20797633). However, this appears to be a secondary role 
      related to its function in maturing Fe-S proteins like XPD rather than a 
      direct role in the segregation machinery.
    action: KEEP_AS_NON_CORE
    reason: While CIAO1's involvement in chromosome segregation via the MMXD 
      complex is documented (PMID:20797633), this is likely an indirect 
      consequence of its role in maturing Fe-S cluster-containing proteins such 
      as XPD that are required for proper chromosome segregation. The core 
      function of CIAO1 is in Fe-S cluster assembly/transfer.
    supported_by:
    - reference_id: PMID:20797633
      supporting_text: MMS19, MIP18, and XPD localized to the mitotic spindle 
        during mitosis. The siRNA-mediated knockdown of MMS19, MIP18, or XPD led
        to improper chromosome segregation
- term:
    id: GO:0016226
    label: iron-sulfur cluster assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: This IEA annotation based on automated methods correctly captures 
      CIAO1's role in iron-sulfur cluster assembly, which is strongly supported 
      by experimental evidence.
    action: ACCEPT
    reason: This is a correct annotation that aligns with the experimentally 
      verified function of CIAO1 in the CIA pathway.
    supported_by:
    - reference_id: PMID:23891004
      supporting_text: CIA2B-CIA1-MMS19 and CIA2A-CIA1 assist different branches
        of Fe/S protein assembly
- term:
    id: GO:0071817
    label: MMXD complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  review:
    summary: CIAO1 was identified as a component of the MMXD complex 
      (MMS19-MIP18-XPD-Ciao1-ANT2) by Ito et al. 2010 (PMID:20797633). This 
      complex functions independently of TFIIH and is involved in chromosome 
      segregation.
    action: ACCEPT
    reason: This annotation is supported by direct experimental evidence from 
      PMID:20797633 demonstrating CIAO1's membership in the MMXD complex.
    supported_by:
    - reference_id: PMID:20797633
      supporting_text: the MMS19-XPD complex did not contain any other subunits 
        of TFIIH. Instead, it included FAM96B (now designated MIP18), Ciao1, and
        ANT2
- term:
    id: GO:0097361
    label: cytosolic [4Fe-4S] assembly targeting complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: This IEA annotation correctly reflects CIAO1's membership in the 
      cytosolic [4Fe-4S] assembly targeting complex, supported by extensive 
      experimental data.
    action: ACCEPT
    reason: Accurate annotation consistent with multiple experimental studies 
      demonstrating CIAO1 is a core component of the CTC.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  review:
    summary: High-throughput protein interaction study. Protein binding is too 
      general and uninformative for CIAO1's specific role as a scaffold/adapter 
      in Fe-S cluster transfer.
    action: MARK_AS_OVER_ANNOTATED
    reason: The term 'protein binding' is non-informative for CIAO1 which has a 
      specific scaffold function in the CIA targeting complex. The actual 
      molecular function involves acting as a client docking platform for Fe-S 
      protein maturation, which is not well captured by this generic term.
    supported_by:
    - reference_id: PMID:16189514
      supporting_text: Towards a proteome-scale map of the human protein-protein
        interaction network.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17353931
  review:
    summary: Large-scale mass spectrometry protein interaction mapping. Shows 
      interaction with MMS19 (Q96T76) but 'protein binding' is too general.
    action: MARK_AS_OVER_ANNOTATED
    reason: While the interaction data is valid, 'protein binding' does not 
      capture the functional significance of CIAO1's role as a scaffold in the 
      CIA targeting complex.
    supported_by:
    - reference_id: PMID:17353931
      supporting_text: Large-scale mapping of human protein-protein interactions
        by mass spectrometry.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21516116
  review:
    summary: Next-generation sequencing interactome study showing interaction 
      with MMS19 and CIAO2B (FAM96B). Generic protein binding annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific interactions are meaningful for understanding CIA 
      complex assembly, but 'protein binding' is too vague to be informative.
    supported_by:
    - reference_id: PMID:21516116
      supporting_text: Next-generation sequencing to generate interactome 
        datasets.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23585563
  review:
    summary: This publication (Seki et al. 2013) demonstrates specific 
      interactions between CIAO1 and ERCC2/XPD, CIAO3/IOP1, and CIAO2B within 
      the CIA complex. These are functionally relevant interactions for Fe-S 
      cluster delivery.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying data is valuable but 'protein binding' is too 
      generic. The interactions represent CIAO1's role as a scaffold in the CIA 
      targeting complex.
    supported_by:
    - reference_id: PMID:23585563
      supporting_text: MIP18 has a role to bridge MMS19 and CIAO1. CIAO1 also 
        binds IOP1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24245804
  review:
    summary: Shows interaction with viperin (RSAD2), an Fe-S protein that is a 
      CIA client. Viperin requires Fe-S cluster for its antiviral activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: The interaction with viperin represents CIAO1's client interaction 
      function, but 'protein binding' is uninformative.
    supported_by:
    - reference_id: PMID:24245804
      supporting_text: Viperin is an iron-sulfur protein that inhibits genome 
        synthesis of tick-borne encephalitis virus via radical SAM domain 
        activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24981860
  review:
    summary: Human chromatin-related protein interaction study showing 
      interactions with MMS19, CIAO2A, and CIAO2B components of the CIA complex.
    action: MARK_AS_OVER_ANNOTATED
    reason: Relevant interactions but generic protein binding term is 
      uninformative.
    supported_by:
    - reference_id: PMID:24981860
      supporting_text: 2014 Jun 26. Human-chromatin-related protein interactions
        identify a demethylase complex required for chromosome segregation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  review:
    summary: Proteome-scale interactome study. Shows multiple interactions 
      including with CIA complex components.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput data; protein binding is too general for curation 
      purposes.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: A proteome-scale map of the human interactome network.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28178521
  review:
    summary: This focused study on the CIA targeting complex demonstrates CIAO1 
      interactions with ERCC2/XPD and MMS19, providing important mechanistic 
      insights into client binding by the CTC.
    action: MARK_AS_OVER_ANNOTATED
    reason: Valuable mechanistic data about CIA targeting complex, but 'protein 
      binding' is too generic. The publication supports the complex membership 
      annotations.
    supported_by:
    - reference_id: PMID:28178521
      supporting_text: The CIA Targeting Complex Is Highly Regulated and 
        Provides Two Distinct Binding Sites for Client Iron-Sulfur Proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  review:
    summary: Architecture of human interactome study showing interaction with 
      MMS19.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome data; protein binding is uninformative.
    supported_by:
    - reference_id: PMID:28514442
      supporting_text: Architecture of the human interactome defines protein 
        communities and disease networks.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32222833
  review:
    summary: This study demonstrates formation of a stable ternary complex of 
      CIAO3, CIAO1, and CIAO2A, with a [4Fe-4S] cluster. Important for 
      understanding CIA machinery.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mechanistically important data, but 'protein binding' does not 
      capture the specific scaffold function of CIAO1 in the CIA complex.
    supported_by:
    - reference_id: PMID:32222833
      supporting_text: the formation of a stable, [4Fe-4S]-bound, complex, 
        composed by CIAO3 and the hetero-CIA2A-CIAO1 complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: Reference map of human binary protein interactome showing multiple 
      CIAO1 interactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome data; protein binding is too general.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: Apr 8. A reference map of the human binary protein 
        interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: Dual proteome-scale network study showing cell-specific CIAO1 
      interactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: Large-scale interaction data; protein binding is uninformative.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: 2021 May 6. Dual proteome-scale networks reveal 
        cell-specific remodeling of the human interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  review:
    summary: Multimodal cell maps study for structural and functional genomics.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput data; protein binding is too general.
    supported_by:
    - reference_id: PMID:40205054
      supporting_text: Apr 9. Multimodal cell maps as a foundation for 
        structural and functional genomics.
- term:
    id: GO:0051604
    label: protein maturation
  evidence_type: IGI
  original_reference_id: PMID:17937914
  review:
    summary: This study on yeast Cia1 structure demonstrates that human CIAO1 
      can functionally replace yeast Cia1 in supporting cytosolic Fe-S protein 
      biogenesis. The protein maturation annotation refers to the maturation of 
      Fe-S proteins through cluster insertion.
    action: MODIFY
    reason: While CIAO1 does participate in protein maturation (specifically of 
      Fe-S proteins), a more precise annotation would be 'iron-sulfur cluster 
      assembly' (GO:0016226) which is already present. The term 'protein 
      maturation' is too general.
    proposed_replacement_terms:
    - id: GO:0016226
      label: iron-sulfur cluster assembly
    supported_by:
    - reference_id: PMID:17937914
      supporting_text: We show that Ciao1 can functionally replace Cia1 and 
        support cytosolic Fe/S protein biogenesis
- term:
    id: GO:0051604
    label: protein maturation
  evidence_type: IMP
  original_reference_id: PMID:23891004
  review:
    summary: This study demonstrates that CIAO1 facilitates assembly/maturation 
      of cytosolic-nuclear Fe-S proteins by participating in cluster insertion. 
      While technically protein maturation, the more specific term 'iron-sulfur 
      cluster assembly' better captures the function.
    action: MODIFY
    reason: The specific function is iron-sulfur cluster insertion into 
      apo-proteins, which is already captured by GO:0016226. 'Protein 
      maturation' is overly broad.
    proposed_replacement_terms:
    - id: GO:0016226
      label: iron-sulfur cluster assembly
    supported_by:
    - reference_id: PMID:23891004
      supporting_text: The CIA2B-CIA1-MMS19 complex binds to and facilitates 
        assembly of most cytosolic-nuclear Fe/S proteins
- term:
    id: GO:0097361
    label: cytosolic [4Fe-4S] assembly targeting complex
  evidence_type: IMP
  original_reference_id: PMID:38950322
  review:
    summary: This landmark 2024 study on CIAO1 loss-of-function patients 
      demonstrates that CIAO1 is essential for CIA complex stability. Loss of 
      CIAO1 leads to destabilization of MMS19 and FAM96B, confirming CIAO1's 
      role as a core CTC component.
    action: ACCEPT
    reason: Strong experimental evidence from patient-derived cells showing 
      CIAO1 is essential for CTC stability and function.
    supported_by:
    - reference_id: PMID:38950322
      supporting_text: CIAO1 protein levels were profoundly diminished in 
        cytosolic lysates from P1-derived fibroblasts compared with parental 
        cells (Figure 4, A and B, and Supplemental Figure 3, A and B), with a 
        concomitant loss of the known CIAO1-interacting partners MMS19 and 
        FAM96B (Figure 4A and Supplemental Figure 3, A and B)
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: NAS
  original_reference_id: PMID:23585563
  review:
    summary: Cytoplasmic localization stated in the context of CIA complex 
      characterization.
    action: ACCEPT
    reason: Consistent with experimental data showing CIAO1 functions in the 
      cytosol as part of the CIA machinery.
    supported_by:
    - reference_id: PMID:23585563
      supporting_text: Epub 2013 Apr 12. IOP1 protein is an external component 
        of the human cytosolic iron-sulfur cluster assembly (CIA) machinery and 
        functions in the MMS19 protein-dependent CIA pathway.
- term:
    id: GO:0016226
    label: iron-sulfur cluster assembly
  evidence_type: NAS
  original_reference_id: PMID:23585563
  review:
    summary: CIAO1's role in iron-sulfur cluster assembly is discussed in the 
      context of the CIA pathway.
    action: ACCEPT
    reason: Accurate annotation supported by the publication's characterization 
      of the CIA complex and CIAO1's role in Fe-S protein maturation.
    supported_by:
    - reference_id: PMID:23585563
      supporting_text: Epub 2013 Apr 12. IOP1 protein is an external component 
        of the human cytosolic iron-sulfur cluster assembly (CIA) machinery and 
        functions in the MMS19 protein-dependent CIA pathway.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: NAS
  original_reference_id: PMID:32222833
  review:
    summary: Cytoplasmic localization in context of CIA complex studies.
    action: ACCEPT
    reason: Consistent with established cytosolic function of CIAO1.
    supported_by:
    - reference_id: PMID:32222833
      supporting_text: Epub 2020 Mar 28. CIAO3 protein forms a stable ternary 
        complex with two key players of the human cytosolic iron-sulfur cluster 
        assembly machinery.
- term:
    id: GO:0016226
    label: iron-sulfur cluster assembly
  evidence_type: IDA
  original_reference_id: PMID:32222833
  review:
    summary: This study demonstrates CIAO1 forms a stable ternary complex with 
      CIAO3 and CIAO2A that is [4Fe-4S]-bound, directly supporting its role in 
      iron-sulfur cluster assembly.
    action: ACCEPT
    reason: Direct experimental evidence showing CIAO1's participation in Fe-S 
      cluster containing complexes.
    supported_by:
    - reference_id: PMID:32222833
      supporting_text: the formation of a stable, [4Fe-4S]-bound, complex, 
        composed by CIAO3 and the hetero-CIA2A-CIAO1 complex
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:23585563
  review:
    summary: Direct experimental evidence for cytoplasmic localization from 
      subcellular fractionation studies.
    action: ACCEPT
    reason: IDA evidence directly demonstrates cytoplasmic localization of 
      CIAO1.
    supported_by:
    - reference_id: PMID:38950322
      supporting_text: the 3 core components of the CIA complex, which 
        specifically localizes to the cytosolic compartment of mammalian cells
    - reference_id: PMID:23585563
      supporting_text: Epub 2013 Apr 12. IOP1 protein is an external component 
        of the human cytosolic iron-sulfur cluster assembly (CIA) machinery and 
        functions in the MMS19 protein-dependent CIA pathway.
- term:
    id: GO:0097361
    label: cytosolic [4Fe-4S] assembly targeting complex
  evidence_type: IDA
  original_reference_id: PMID:23585563
  review:
    summary: Direct demonstration of CIAO1 as a core component of the CTC 
      through co-immunoprecipitation and biochemical studies.
    action: ACCEPT
    reason: Strong experimental evidence showing CIAO1 is a core CTC component.
    supported_by:
    - reference_id: PMID:23585563
      supporting_text: Here, we show that MMS19, MIP18, and CIAO1 form a tight 
        "core" complex and that IOP1 is an "external" component of this complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23891004
  review:
    summary: This study demonstrates specific interactions between CIAO1 and 
      multiple CIA components (CIAO2A, CIAO2B, MMS19) and client Fe-S proteins 
      (ERCC2, POLD1, IREB2).
    action: MARK_AS_OVER_ANNOTATED
    reason: The interactions are highly relevant for understanding CIA function,
      but 'protein binding' is too generic to be informative. The complex 
      membership annotations better capture these functional relationships.
    supported_by:
    - reference_id: PMID:23891004
      supporting_text: CIA1 associates with either CIA2A or CIA2B and the 
        CIA-targeting factor MMS19
- term:
    id: GO:0097361
    label: cytosolic [4Fe-4S] assembly targeting complex
  evidence_type: IDA
  original_reference_id: PMID:23891004
  review:
    summary: Comprehensive characterization of CIAO1 as a core component of the 
      CTC, showing it forms distinct complexes with CIAO2A-CIAO1 and 
      CIAO2B-CIAO1-MMS19.
    action: ACCEPT
    reason: Key publication establishing CIAO1's role in the CIA targeting 
      complex.
    supported_by:
    - reference_id: PMID:23891004
      supporting_text: CIA2B-CIA1-MMS19 and CIA2A-CIA1 assist different branches
        of Fe/S protein assembly
- term:
    id: GO:0097361
    label: cytosolic [4Fe-4S] assembly targeting complex
  evidence_type: IDA
  original_reference_id: PMID:22678361
  review:
    summary: This Science paper demonstrates MMS19 forms a complex with CIAO1 
      and other CIA factors (IOP1/CIAO3, MIP18/CIAO2B) that links cytoplasmic 
      Fe-S assembly to DNA metabolism.
    action: ACCEPT
    reason: Landmark study establishing the CIA targeting complex.
    supported_by:
    - reference_id: PMID:22678361
      supporting_text: MMS19 forms a complex with the cytoplasmic Fe-S assembly 
        (CIA) proteins CIAO1, IOP1, and MIP18
- term:
    id: GO:0097361
    label: cytosolic [4Fe-4S] assembly targeting complex
  evidence_type: IDA
  original_reference_id: PMID:22678362
  review:
    summary: Companion Science paper demonstrating MMS19 as part of the CIA 
      targeting complex that facilitates Fe-S cluster insertion into DNA 
      metabolism proteins.
    action: ACCEPT
    reason: Foundational study for understanding the CTC and CIAO1's role in it.
    supported_by:
    - reference_id: PMID:22678362
      supporting_text: MMS19 functions as part of the CIA targeting complex that
        specifically interacts with and facilitates iron-sulfur cluster 
        insertion into apoproteins
- term:
    id: GO:0071817
    label: MMXD complex
  evidence_type: IDA
  original_reference_id: PMID:20797633
  review:
    summary: Direct identification of CIAO1 as a component of the MMXD complex 
      (MMS19-MIP18-XPD-Ciao1-ANT2) through immunoprecipitation studies.
    action: ACCEPT
    reason: Experimental evidence directly demonstrating CIAO1 is part of the 
      MMXD complex.
    supported_by:
    - reference_id: PMID:20797633
      supporting_text: the MMS19-XPD complex did not contain any other subunits 
        of TFIIH. Instead, it included FAM96B (now designated MIP18), Ciao1, and
        ANT2
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: TAS
  original_reference_id: PMID:9556563
  review:
    summary: The original 1998 CIAO1 paper identified it as a WT1-interacting 
      protein that modulates WT1 transactivation activity. However, this was 
      before CIAO1's primary role in Fe-S cluster assembly was understood. The 
      effect on transcription is likely indirect through Fe-S protein 
      maturation.
    action: KEEP_AS_NON_CORE
    reason: While CIAO1 was originally identified as interacting with WT1 and 
      modulating its transcriptional activity (PMID:9556563), this is now 
      understood as a secondary/indirect effect. CIAO1's primary function is in 
      the CIA pathway for Fe-S cluster assembly. The transcriptional effects may
      relate to Fe-S cluster-dependent transcription factors or chromatin 
      modifiers.
    supported_by:
    - reference_id: PMID:9556563
      supporting_text: Ciao 1 appears to specifically modulate the 
        transactivation activity of WT1
- term:
    id: GO:0140132
    label: iron-sulfur cluster chaperone activity
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations.
    supported_by:
    - reference_id: PMID:23891004
      supporting_text: The CIA2B-CIA1-MMS19 complex binds to and facilitates 
        assembly of most cytosolic-nuclear Fe/S proteins
    - reference_id: PMID:38950322
      supporting_text: CIAO1 is a key component of the CIA machinery
core_functions:
- description: CIAO1 is a core component of the cytosolic iron-sulfur assembly 
    (CIA) targeting complex that facilitates transfer of [4Fe-4S] clusters to 
    cytosolic and nuclear Fe-S proteins. Multiple independent studies confirm 
    this role (PMID:22678361, PMID:22678362, PMID:23891004, PMID:23585563, 
    PMID:38950322). Loss of CIAO1 results in compromised Fe-S protein 
    maturation.
  molecular_function:
    id: GO:0140132
    label: iron-sulfur cluster chaperone activity
  directly_involved_in:
  - id: GO:0016226
    label: iron-sulfur cluster assembly
  locations:
  - id: GO:0005737
    label: cytoplasm
  in_complex:
    id: GO:0097361
    label: cytosolic [4Fe-4S] assembly targeting complex
  supported_by:
  - reference_id: PMID:23891004
    supporting_text: The CIA2B-CIA1-MMS19 complex binds to and facilitates 
      assembly of most cytosolic-nuclear Fe/S proteins
  - reference_id: PMID:38950322
    supporting_text: CIAO1 is a key component of the CIA machinery
proposed_new_terms: []
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
    Location vocabulary mapping, accompanied by conservative changes to GO terms
    applied by UniProt
  findings: []
- id: GO_REF:0000104
  title: Electronic Gene Ontology annotations created by transferring manual GO 
    annotations between related proteins based on shared sequence features
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction 
    network.
  findings: []
- id: PMID:17353931
  title: Large-scale mapping of human protein-protein interactions by mass 
    spectrometry.
  findings: []
- id: PMID:17937914
  title: Structure of the yeast WD40 domain protein Cia1, a component acting 
    late in iron-sulfur protein biogenesis.
  findings:
  - statement: Human CIAO1 can functionally replace yeast Cia1 in supporting 
      cytosolic Fe-S protein biogenesis
  - statement: Crystal structure of Cia1 reveals a 7-bladed beta-propeller WD40 
      domain
- id: PMID:20797633
  title: MMXD, a TFIIH-independent XPD-MMS19 protein complex involved in 
    chromosome segregation.
  findings:
  - statement: CIAO1 is a component of the MMXD complex 
      (MMS19-MIP18-XPD-CIAO1-ANT2)
  - statement: MMXD localizes to the mitotic spindle during mitosis
  - statement: Knockdown leads to improper chromosome segregation
- id: PMID:21516116
  title: Next-generation sequencing to generate interactome datasets.
  findings: []
- id: PMID:22678361
  title: MMS19 links cytoplasmic iron-sulfur cluster assembly to DNA metabolism.
  findings:
  - statement: MMS19 forms a complex with CIAO1, IOP1, and MIP18
  - statement: This complex facilitates Fe-S cluster transfer to DNA metabolism 
      proteins
  - statement: MMS19 knockout is preimplantation lethal in mice
- id: PMID:22678362
  title: MMS19 assembles iron-sulfur proteins required for DNA metabolism and 
    genomic integrity.
  findings:
  - statement: MMS19 is part of the CIA targeting complex
  - statement: The complex facilitates Fe-S cluster insertion into proteins for 
      DNA replication and repair
- id: PMID:23585563
  title: IOP1 protein is an external component of the human cytosolic 
    iron-sulfur cluster assembly (CIA) machinery and functions in the MMS19 
    protein-dependent CIA pathway.
  findings:
  - statement: MMS19, MIP18, and CIAO1 form a tight core complex
  - statement: IOP1/CIAO3 is an external component
  - statement: CIAO1 binds IOP1
- id: PMID:23891004
  title: Human CIA2A-FAM96A and CIA2B-FAM96B integrate iron homeostasis and 
    maturation of different subsets of cytosolic-nuclear iron-sulfur proteins.
  findings:
  - statement: CIAO1 associates with either CIAO2A or CIAO2B
  - statement: CIA2B-CIA1-MMS19 complex matures most cytosolic-nuclear Fe-S 
      proteins
  - statement: CIA2A-CIA1 specifically matures ACO1/IRP1 and stabilizes IRP2
- id: PMID:24245804
  title: Viperin is an iron-sulfur protein that inhibits genome synthesis of 
    tick-borne encephalitis virus via radical SAM domain activity.
  findings: []
- id: PMID:24981860
  title: Human-chromatin-related protein interactions identify a demethylase 
    complex required for chromosome segregation.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:28178521
  title: The CIA Targeting Complex Is Highly Regulated and Provides Two Distinct
    Binding Sites for Client Iron-Sulfur Proteins.
  findings:
  - statement: CTC provides two distinct client binding sites
  - statement: Complex is highly regulated
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and 
    disease networks.
  findings: []
- id: PMID:32222833
  title: CIAO3 protein forms a stable ternary complex with two key players of 
    the human cytosolic iron-sulfur cluster assembly machinery.
  findings:
  - statement: CIAO3, CIAO1, and CIAO2A form a stable [4Fe-4S]-bound ternary 
      complex
  - statement: C-terminal [4Fe-4S] cluster of CIAO3 has structural role
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the 
    human interactome.
  findings: []
- id: PMID:38950322
  title: CIAO1 loss of function causes a neuromuscular disorder with compromise 
    of nucleocytoplasmic Fe-S enzymes.
  findings:
  - statement: Biallelic CIAO1 loss-of-function causes MMDS10 (MIM 620960)
  - statement: Patients have proximal muscle weakness, respiratory 
      insufficiency, learning difficulties
  - statement: CIAO1 loss destabilizes MMS19 and FAM96B
  - statement: Multiple nucleocytoplasmic Fe-S enzymes are compromised (POLD1, 
      DPYD, etc.)
  - statement: Lentiviral CIAO1 restoration rescues all cellular defects
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional 
    genomics.
  findings: []
- id: PMID:9556563
  title: Ciao 1 is a novel WD40 protein that interacts with the tumor suppressor
    protein WT1.
  findings:
  - statement: Original identification of CIAO1 as a WT1-interacting protein
  - statement: CIAO1 modulates WT1 transactivation activity
  - statement: Does not affect WT1 DNA binding or repression activity
- id: file:human/CIAO1/CIAO1-deep-research-falcon.md
  title: Deep research report on CIAO1 function
  findings:
  - statement: CIAO1 is a WD40/beta-propeller protein and core component of the 
      late-acting CIA machinery
  - statement: A conserved C-terminal tripeptide TCR motif encodes specificity 
      for CIA client targeting
  - statement: CIAO1 loss-of-function variants cause a neuromuscular disorder 
      with selective compromise of nucleocytoplasmic Fe-S enzymes
tags:
- iron-sulfur-cluster-biogenesis

CIAO1

Gene Description

Existing Annotations Review

Core Functions

References

Tags

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

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