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Showing CIAO2B — FAM96B is a alias.

CIAO2B

Cytosolic iron-sulfur assembly component 2B · UniProt Q9Y3D0

Length
163 aa
Mass
17.7 kDa
Annotated
2026-06-09
33 papers in source corpus 18 papers cited in narrative 18 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CIAO2B (FAM96B/MIP18/CIA2B) is the central scaffolding subunit of the cytosolic iron-sulfur (Fe-S) cluster assembly (CIA) targeting complex, which delivers Fe-S clusters to a broad range of cytosolic and nuclear client proteins (PMID:23150669, PMID:23891004). Within the core CIA targeting complex, CIAO2B is centrally located and bridges CIAO1 and MMS19, with crystal and cryo-EM structures defining a bipartite client recognition mode in which CIAO1 and the structural flexibility of MMS19 engage substrates such as primase and DNA2 (PMID:32632277). The three core subunits are mutually stabilizing—knockdown of any one down-regulates the others, and direct MMS19 binding protects CIAO2B from proteasomal degradation (PMID:23585563, PMID:28178521). Through this complex CIAO2B targets Fe-S clusters to DNA metabolism enzymes including XPD, which must be matured cytoplasmically by the CIA targeting complex before incorporation into nuclear TFIIH (PMID:25897079), and the chromokinesin KIF4A, an Fe-S client whose maturation links CIAO2B to mitotic spindle organization and faithful chromosome segregation (PMID:20797633, PMID:29848660). CIAO2B also couples Fe-S biogenesis to cellular iron homeostasis: its depletion stabilizes IRP2, and the CIA targeting complex interacts with FBXL5 to promote oxygen-dependent degradation of iron regulatory proteins (PMID:23891004, PMID:31229404). Loss of CIA core function compromises the activities of DNA helicases, polymerases, and repair enzymes, and the CIAO2B ortholog is essential for development and for stability of the FANCJ helicase DOG-1/BRIP1 (PMID:39011897, PMID:38950322).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2010 High

    Established that CIAO2B (MIP18) is part of a spindle-associated complex with functional consequences, answering whether the protein had a defined cellular role.

    Evidence Co-IP, siRNA knockdown and mitotic spindle immunofluorescence defining the MMXD (MMS19-MIP18-XPD) complex

    PMID:20797633

    Open questions at the time
    • Did not define the biochemical activity underlying the segregation defect
    • Connection to Fe-S cluster biology not yet established
  2. 2012 High

    Placed CIAO2B in the cytosolic Fe-S cluster assembly pathway, defining its molecular function as a delivery scaffold rather than a generic spindle factor.

    Evidence Co-IP, pulldown and in vitro binding showing MIP18 bridges CIAO1 and binds Fe-S coordinating regions of clients, within an MMS19-CIAO1-MIP18 complex

    PMID:22678361 PMID:23150669

    Open questions at the time
    • Stoichiometry and architecture of the complex unresolved
    • Mechanism of cluster transfer not defined
  3. 2013 High

    Linked the CIAO2B complex to cellular iron regulation, showing its function extends beyond client maturation to iron homeostasis sensing.

    Evidence Co-IP, 55Fe radiolabeling and siRNA depletion showing CIA2B loss stabilizes IRP2 and impairs Fe-S assembly into most cytosolic-nuclear targets

    PMID:23891004

    Open questions at the time
    • Mechanism connecting CIA2B loss to IRP2 stabilization not yet molecularly defined
  4. 2013 High

    Defined CIAO2B as the bridging subunit of a co-dependent core complex, clarifying complex topology and subunit interdependence.

    Evidence siRNA knockdown, Co-IP and in vitro binding distinguishing the tight MMS19-MIP18-CIAO1 core from the external IOP1 component

    PMID:23585563

    Open questions at the time
    • High-resolution structure of the bridge interface not yet available
  5. 2015 High

    Demonstrated a sequential, compartmentalized maturation step, showing the CIA targeting complex acts cytoplasmically before nuclear client assembly.

    Evidence Co-IP, subcellular fractionation, iron depletion and XPD binding mutants showing mutually exclusive association of XPD with the CIA complex or TFIIH

    PMID:25897079

    Open questions at the time
    • Spatial/temporal trigger for handoff to nuclear partners unresolved
  6. 2017 Medium

    Mapped the client docking site to the MMS19 C terminus and established that CIAO2B stability depends on MMS19 binding, explaining subunit co-regulation.

    Evidence Co-IP, truncation mapping and proteasome inhibitor rescue, with XPD shown to bind MMS19 independently of MIP18/CIAO1

    PMID:28178521

    Open questions at the time
    • Single lab; degradation pathway and E3 ligase for unprotected MIP18 not identified
  7. 2017 High

    Refined client specificity, showing CIAO2B is not required for all CIA clients (e.g. viperin maturation depends predominantly on CIA1).

    Evidence Co-IP domain mapping and 55Fe radiolabeling with selective CIA factor depletion on viperin/RSAD2

    PMID:28615450

    Open questions at the time
    • Determinants that route clients to CIAO2B-dependent vs independent paths unknown
  8. 2018 High

    Identified a defined mitotic Fe-S client (KIF4A), mechanistically connecting CIAO2B's Fe-S delivery to its long-known spindle phenotype.

    Evidence siRNA knockdown, in vitro Fe-S binding, immunofluorescence colocalization and KIF4A cysteine-rich domain mutants

    PMID:29848660

    Open questions at the time
    • Whether spindle phenotypes arise solely through KIF4A or additional mitotic clients unresolved
  9. 2018 Medium

    Connected de novo Fe-S biosynthesis to CIA targeting, showing how clusters reach the CIAO2B complex.

    Evidence Co-IP, siRNA knockdown and 55Fe radiolabeling implicating cytosolic HSC20 in bridging ISC components to the CIA targeting complex

    PMID:29309586

    Open questions at the time
    • Single lab; direct biochemical reconstitution of cluster transfer not shown
  10. 2019 High

    Mechanistically tied the CIAO2B complex to oxygen-dependent iron regulation via FBXL5.

    Evidence Co-IP, IRP degradation assays and oxygen tension manipulation showing FBXL5-CIA targeting complex interaction is oxygen-sensitive

    PMID:31229404

    Open questions at the time
    • Structural basis of the FBXL5 interaction not defined
  11. 2020 High

    Provided atomic-level architecture, defining how CIAO2B bridges the complex and how clients are recognized and matured.

    Evidence X-ray crystallography, cryo-EM of CTC bound to primase/DNA2, biophysical assays and yeast complementation revealing a bipartite client recognition mode

    PMID:32632277

    Open questions at the time
    • The ~70 Å separation between client cluster and reactive cysteine implies conformational dynamics not directly visualized
    • Transfer intermediate states unresolved
  12. 2022 Medium

    Extended CIAO2B's higher-order assembly, situating the targeting complex within an iron-regulated CIA metabolon.

    Evidence Targeted proteomics, Co-IP and CIAO3 Fe-S binding mutants with iron supplementation/chelation

    PMID:35654137

    Open questions at the time
    • Weak NUBP2 association; functional role of metabolon assembly not established
  13. 2024 Medium

    Demonstrated organismal essentiality and a specific repair-enzyme client in vivo, distinguishing CIAO2B from MMS19.

    Evidence C. elegans deletion mutants, DNA damage sensitivity, epistasis and DOG-1 (FANCJ/BRIP1) stability assays

    PMID:39011897

    Open questions at the time
    • Single ortholog system; whether human CIAO2B is similarly essential not directly tested here
  14. 2024 High

    Confirmed in human disease context that the CIAO2B-containing core complex is required to mature DNA metabolism enzymes.

    Evidence Patient-derived cells, functional Fe-S enzyme assays and lentiviral CIAO1 rescue showing impaired recruitment of Fe-S recipients to the CIAO1-MMS19-FAM96B complex

    PMID:38950322

    Open questions at the time
    • Disease evidence centers on CIAO1; direct CIAO2B patient mutations not described here

Open questions

Synthesis pass · forward-looking unresolved questions
  • How conformational dynamics drive the actual Fe-S cluster transfer step from the CTC reactive cysteine to distant client clusters, and what governs client routing through CIAO2B-dependent versus independent paths, remain unresolved.
  • No captured transfer intermediate structure
  • Rules for client specificity not defined
  • Reconstituted transfer reaction not reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3
Localization
GO:0005815 microtubule organizing center 2 GO:0005829 cytosol 2
Pathway
R-HSA-1640170 Cell Cycle 2 R-HSA-73894 DNA Repair 2 GO:0140657 ATP-dependent activity 1
Partners
CIAO1CKBFBXL5KIF4AMMS19NUBP2RSAD2XPD
Complex memberships
CIA targeting complex (CIAO1-MMS19-FAM96B)MMXD complex (MMS19-MIP18-XPD)

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 FAM96B (MIP18) was identified as a component of the MMXD complex (MMS19-MIP18-XPD) that localizes to the mitotic spindle during mitosis; siRNA-mediated knockdown of MIP18 led to improper chromosome segregation and accumulation of nuclei with abnormal shapes, establishing its role in chromosome segregation. Co-immunoprecipitation, siRNA knockdown, immunofluorescence localization to mitotic spindle, phenotypic analysis of chromosome segregation defects Molecular cell High 20797633
2012 MIP18 (FAM96B) forms a core complex with MMS19 and CIAO1 in the cytoplasmic iron-sulfur cluster assembly (CIA) pathway; MIP18 interacts with both CIAO1 and Fe-S proteins by binding their Fe-S cluster-coordinating regions, functioning in Fe-S cluster delivery to cytoplasmic and nuclear proteins. Co-immunoprecipitation, pulldown assays, in vivo and in vitro binding experiments The Journal of biological chemistry High 23150669
2012 MMS19 forms a complex with CIA proteins CIAO1, IOP1, and MIP18 (FAM96B) in the cytoplasm; this complex binds multiple nuclear Fe-S proteins involved in DNA metabolism, and loss of MMS19 results in failure to transfer Fe-S clusters to target proteins and Fe-S protein instability. Co-immunoprecipitation, mass spectrometry, mouse knockout (preimplantation lethal), Fe-S protein stability assays Science (New York, N.Y.) High 22678361
2013 CIA2B (FAM96B) associates with CIA1 (CIAO1) and MMS19 to form the CIA2B-CIA1-MMS19 complex, which binds to and facilitates Fe-S cluster assembly into most cytosolic-nuclear Fe-S proteins; depletion of CIA2B leads to stabilization of IRP2 (which lacks an Fe-S cluster), linking CIA2B to cellular iron regulation. Co-immunoprecipitation, 55Fe radiolabeling, siRNA knockdown, functional Fe-S assembly assays Cell metabolism High 23891004
2013 MMS19, MIP18 (FAM96B), and CIAO1 form a tight 'core' CIA complex; IOP1 is an 'external' component that interacts with the core complex both in vivo and in vitro but behaves differently—knockdown of core components leads to down-regulation of all core components, whereas IOP1 knockdown does not affect core component levels. MIP18 bridges MMS19 and CIAO1 within the core complex. siRNA knockdown, co-immunoprecipitation, in vitro binding assays, protein level analysis The Journal of biological chemistry High 23585563
2015 The CIA targeting complex composed of MMS19, CIAO1, and FAM96B (CIA2B) is required for Fe-S cluster assembly onto XPD before its incorporation into TFIIH; XPD associates in a mutually exclusive fashion with either the CIA targeting complex (in the cytoplasm) or TFIIH (in the nucleus), establishing a sequential cytoplasmic Fe-S assembly step before nuclear TFIIH assembly. Co-immunoprecipitation, subcellular fractionation, iron depletion experiments, XPD point mutants defective in Fe-S or CIA complex binding The Journal of biological chemistry High 25897079
2017 MIP18 (FAM96B) and CIAO1 associate with the C terminus of MMS19 to form a docking site for Fe-S client proteins; direct interaction between MMS19 and MIP18 is required to protect MIP18 from proteasomal degradation. XPD can interact with MMS19 independently of MIP18 and CIAO1, representing an exception. Co-immunoprecipitation, proteasomal inhibitor treatment, truncation/deletion mapping experiments Cell reports Medium 28178521
2017 CIA2B (FAM96B) and MMS19 physically interact with the C terminus of viperin (RSAD2) using CIA1 as the primary viperin-interacting protein to facilitate Fe-S cluster insertion into viperin; CIA2A binds viperin's N terminus independently of CIA1, CIA2B, and MMS19. Depletion of CIA1, but not CIA2B or MMS19, predominantly impairs 55Fe/S cluster incorporation into viperin. Co-immunoprecipitation, 55Fe radiolabeling in human cells depleted of CIA factors by siRNA The Journal of biological chemistry High 28615450
2018 CIA2B (FAM96B) and MMS19, constituents of the CIA targeting complex, colocalize with components of the mitotic machinery; downregulation of CIA2B and MMS19 impairs the mitotic cycle. The chromokinesin KIF4A was identified as a mitotic Fe-S client—KIF4A binds an Fe-S cluster in vitro through its conserved cysteine-rich domain, and this domain is required for mitosis-related KIF4A localization, linking CIA2B-mediated Fe-S cluster delivery to mitotic defects. siRNA knockdown, in vitro Fe-S cluster binding assay, immunofluorescence colocalization, KIF4A knockout and cysteine-rich domain mutant analysis Journal of cell science High 29848660
2018 Cytosolic HSC20 (C-HSC20) mediates complex formation between ISC pathway components (ISCU1, NFS1) and the CIA targeting complex (CIAO1, FAM96B, MMS19) to facilitate Fe-S cluster insertion into cytoplasmic and nuclear Fe-S recipient proteins, integrating de novo Fe-S biosynthesis with CIA targeting. Co-immunoprecipitation, siRNA knockdown, 55Fe radiolabeling Human molecular genetics Medium 29309586
2019 FBXL5 interacts with the CIA targeting complex (MMS19, FAM96B/CIA2B, and CIAO1); this interaction promotes FBXL5-mediated degradation of iron regulatory proteins (IRPs) and is regulated by oxygen tension—robust at 21% O2 but severely diminished at 1% O2, linking the CIA targeting complex to oxygen-dependent iron homeostasis. Co-immunoprecipitation, IRP degradation assays, oxygen tension manipulation experiments Molecular cell High 31229404
2020 Crystal structures of the CIA targeting complex (CTC) revealed that CIAO2B (FAM96B) is centrally located and bridges CIAO1 and MMS19; cryo-EM reconstructions of CTC bound to primase or DNA2 revealed an evolutionarily conserved bipartite client recognition mode facilitated by CIAO1 and structural flexibility of MMS19. The primase Fe-S cluster is located ~70 Å from the CTC reactive cysteine, implicating conformational dynamics in Fe-S cluster transfer. X-ray crystallography, cryo-EM, biochemical assays, biophysical methods, yeast complementation assays Nature structural & molecular biology High 32632277
2011 FAM96B was identified as an interaction partner of the transcription factor E2-2 in endothelial cells; FAM96B interfered with E2-2-mediated transcriptional repression of a luciferase reporter and rescued E2-2-suppressed VEGFR2 promoter activity in a dose-dependent manner. FAM96B also decreased E2-2 protein expression, with the middle region of FAM96B required for this effect. FAM96B expression in endothelial cells potentiated migration, proliferation, and tube formation. Co-immunoprecipitation, luciferase reporter assays, FAM96B mutational analysis, endothelial cell functional assays (migration, proliferation, tube formation) Cancer science Medium 21722264
2022 Fam96b (MIP18) directly binds brain-type creatine kinase (CKB); this binding is independent of CKB substrates and does not interfere with CKB activity. Fam96b oligomerizes via intermolecular disulfide bonds, and enzymatically active CKB modulates Fam96b oligomerization. Oligomerized Fam96b recruits CKB and the MMXD complex to the mitotic spindle. Depletion of Fam96b by siRNA leads to mitotic defects, retarded proliferation, increased cell death, and aberrant cell cycle progression; both Fam96b oligomerization and CKB activity were required for proper mitotic spindle formation. Co-immunoprecipitation, pulldown, disulfide bond analysis, siRNA knockdown, rescue experiments, immunofluorescence Biochimica et biophysica acta. Molecular cell research Medium 36503010
2022 Iron availability regulates assembly of the CIA machinery: the CIA targeting complex (MMS19, CIAO1, CIAO2B/FAM96B) weakly associates with the CIA scaffold component NUBP2, suggesting a higher-order CIA metabolon. CIAO3 mutants defective in Fe-S cluster binding fail to integrate into higher-order CIA complexes but exhibit stronger associations with CIA substrates, indicating Fe-S cluster incorporation in CIAO3 is required for full CIA metabolon assembly. Targeted proteomics (PRM), co-immunoprecipitation, CIAO3 Fe-S binding mutants, iron supplementation/chelation experiments The Journal of biological chemistry Medium 35654137
2024 CIAO-2B is vital for DOG-1 (FANCJ/BRIP1) stability and DNA repair functions in C. elegans; unlike MMS-19, CIAO-2B has an essential role in C. elegans development. Loss of CIAO-2B results in DOG-1 instability and impaired genome integrity. C. elegans genetics (deletion mutants), DNA damage sensitivity assays, epistasis analysis, protein stability assays Nucleic acids research Medium 39011897
2024 Loss of CIAO1 function in patients impairs recruitment of Fe-S recipient proteins to the CIA core complex (CIAO1-MMS19-FAM96B), resulting in compromised activities of DNA helicases, polymerases, and repair enzymes; lentivirus-mediated restoration of CIAO1 expression reversed patient-derived cellular abnormalities, confirming FAM96B-containing CIA complex is essential for Fe-S delivery to DNA metabolism enzymes. Patient-derived cell studies, mutational analysis, functional Fe-S enzyme activity assays, lentiviral rescue experiments The Journal of clinical investigation High 38950322
2019 FAM96B was identified as a direct binding partner of selenoprotein W (SelW) in the brain; interaction confirmed by yeast two-hybrid screening, FRET analysis, pulldown assay with recombinant proteins, and co-immunoprecipitation from murine brain tissue. Yeast two-hybrid, FRET, pulldown assay, co-immunoprecipitation from brain tissue Biochemical and biophysical research communications Low 30876693

Source papers

Stage 0 corpus · 33 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 MMS19 links cytoplasmic iron-sulfur cluster assembly to DNA metabolism. Science (New York, N.Y.) 194 22678361
2013 Human CIA2A-FAM96A and CIA2B-FAM96B integrate iron homeostasis and maturation of different subsets of cytosolic-nuclear iron-sulfur proteins. Cell metabolism 142 23891004
2013 The iron-sulfur cluster assembly machineries in plants: current knowledge and open questions. Frontiers in plant science 129 23898337
2020 Outlining the Complex Pathway of Mammalian Fe-S Cluster Biogenesis. Trends in biochemical sciences 109 32311335
2010 MMXD, a TFIIH-independent XPD-MMS19 protein complex involved in chromosome segregation. Molecular cell 104 20797633
2018 Cytosolic HSC20 integrates de novo iron-sulfur cluster biogenesis with the CIAO1-mediated transfer to recipients. Human molecular genetics 39 29309586
2012 The mammalian proteins MMS19, MIP18, and ANT2 are involved in cytoplasmic iron-sulfur cluster protein assembly. The Journal of biological chemistry 39 23150669
2013 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. The Journal of biological chemistry 37 23585563
2017 Cellular requirements for iron-sulfur cluster insertion into the antiviral radical SAM protein viperin. The Journal of biological chemistry 35 28615450
2003 Characterization of multiple promoters in the human carboxylesterase 2 gene. Pharmacogenetics 35 12835618
2019 An Oxygen-Dependent Interaction between FBXL5 and the CIA-Targeting Complex Regulates Iron Homeostasis. Molecular cell 34 31229404
2015 The Association of the Xeroderma Pigmentosum Group D DNA Helicase (XPD) with Transcription Factor IIH Is Regulated by the Cytosolic Iron-Sulfur Cluster Assembly Pathway. The Journal of biological chemistry 34 25897079
2020 Structural insights into Fe-S protein biogenesis by the CIA targeting complex. Nature structural & molecular biology 33 32632277
2017 The CIA Targeting Complex Is Highly Regulated and Provides Two Distinct Binding Sites for Client Iron-Sulfur Proteins. Cell reports 29 28178521
2020 FAM96B inhibits the senescence of dental pulp stem cells. Cell biology international 20 32039527
2018 Fe-S cluster coordination of the chromokinesin KIF4A alters its subcellular localization during mitosis. Journal of cell science 17 29848660
2014 Crumbs interacts with Xpd for nuclear division control in Drosophila. Oncogene 16 25065591
2024 CIAO1 loss of function causes a neuromuscular disorder with compromise of nucleocytoplasmic Fe-S enzymes. The Journal of clinical investigation 13 38950322
2022 Iron-regulated assembly of the cytosolic iron-sulfur cluster biogenesis machinery. The Journal of biological chemistry 13 35654137
2021 The cytosolic iron-sulfur cluster assembly (CIA) pathway is required for replication stress tolerance of cancer cells to Chk1 and ATR inhibitors. NPJ breast cancer 11 34857765
2019 Nkx2-5 Second Heart Field Target Gene Ccdc117 Regulates DNA Metabolism and Proliferation. Scientific reports 10 30742009
2011 Interference of E2-2-mediated effect in endothelial cells by FAM96B through its limited expression of E2-2. Cancer science 10 21722264
2022 FAM96A and FAM96B function as new tumor suppressor genes in breast cancer through regulation of the Wnt/β-catenin signaling pathway. Life sciences 9 36165859
2012 Backbone resonance assignments of the monomeric DUF59 domain of human Fam96a. Biomolecular NMR assignments 8 22618863
2022 Crosstalk of Brucella abortus nucleomodulin BspG and host DNA replication process/mitochondrial respiratory pathway promote anti-apoptosis and infection. Veterinary microbiology 7 35395545
2024 Iron‑sulfur clusters in viral proteins: Exploring their elusive nature, roles and new avenues for targeting infections. Biochimica et biophysica acta. Molecular cell research 6 38599324
2024 FAM96B negatively regulates FOSL1 to modulate the osteogenic differentiation and regeneration of periodontal ligament stem cells via ferroptosis. Stem cell research & therapy 6 39696611
2020 Ciao1 interacts with Crumbs and Xpd to regulate organ growth in Drosophila. Cell death & disease 5 32404863
2024 A transcriptome-wide association study identified susceptibility genes for hepatocellular carcinoma in East Asia. Gastroenterology report 4 38846986
2022 Fam96b recruits brain-type creatine kinase to fuel mitotic spindle formation. Biochimica et biophysica acta. Molecular cell research 3 36503010
2019 Identification of FAM96B as a novel selenoprotein W binding partner in the brain. Biochemical and biophysical research communications 3 30876693
2024 The critical role of the iron-sulfur cluster and CTC components in DOG-1/BRIP1 function in Caenorhabditis elegans. Nucleic acids research 1 39011897
2026 Iron-sulfur cofactors in nucleic acid metabolism and protein synthesis: Assembly, delivery, and putative roles in cellular and viral systems. The Journal of biological chemistry 0 42107644

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