Affinage

KIAA0753

Protein moonraker · UniProt Q2KHM9

Length
967 aa
Mass
109.4 kDa
Annotated
2026-06-10
12 papers in source corpus 7 papers cited in narrative 7 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

KIAA0753 (OFIP/MNR) is a centrosomal and pericentriolar satellite protein required for primary ciliogenesis and ciliary signaling (PMID:26643951, PMID:34523780). It forms a ternary complex with OFD1 and FOR20, where loss of any component disrupts centrosomal recruitment of the others, and it possesses intrinsic microtubule-stabilizing activity (PMID:26643951); at the distal centriole it assembles into the DISCO complex with CEP90 and OFD1 [PMID:bio_10.1101_2025.06.17.660204]. CEP120 directly recruits KIAA0753 to centrioles, a step necessary for granule neuron progenitor differentiation in the developing cerebellum (PMID:34711653). Through its role in cilium assembly, KIAA0753 supports Sonic Hedgehog pathway activation, and its ablation blocks ciliogenesis and blunts SHH signaling (PMID:34523780); it further promotes osteoblast differentiation by interacting with SHH and Gli2 and protecting Gli2 from ubiquitination-mediated degradation (PMID:39245790). Its abundance and centrosomal localization are controlled in a cell-type-specific manner by UFL1-catalyzed UFMylation, which limits OFIP stability (PMID:40059580). Loss-of-function KIAA0753 mutations cause defective ciliogenesis in patient fibroblasts, linking the gene to oral-facial-digital/ciliopathy phenotypes (PMID:26643951, PMID:28220259).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2015 High

    Established KIAA0753/OFIP as a centrosome/satellite protein operating within a defined ternary complex, answering how it is organized at the centrosome and what biochemical activity it carries.

    Evidence Reciprocal co-IP, immunofluorescence and siRNA recruitment phenotypes in RPE1 cells plus a microtubule stabilization assay

    PMID:26643951

    Open questions at the time
    • Mechanism by which microtubules are stabilized not resolved
    • Structural basis of the OFD1/FOR20 ternary complex unknown
  2. 2017 Medium

    Connected KIAA0753 loss-of-function directly to a human ciliopathy phenotype, showing the protein is required for primary cilium formation in patient cells.

    Evidence Whole exome sequencing of affected siblings followed by ciliation assays in patient fibroblasts

    PMID:28220259

    Open questions at the time
    • Single lab, one ciliation method
    • Molecular step in ciliogenesis affected not defined
  3. 2021 High

    Identified CEP120 as the direct factor that recruits KIAA0753 to centrioles and tied this interaction to neuronal differentiation, explaining an upstream determinant of its localization.

    Evidence Co-IP plus in vivo cerebellar GNP depletion and wild-type vs. Joubert-mutant CEP120 rescue experiments

    PMID:34711653

    Open questions at the time
    • Whether recruitment is constitutive or regulated not addressed
    • Direct binding interface not mapped
  4. 2021 Medium

    Placed KIAA0753 functionally upstream of SHH (and WNT) signaling, showing that its requirement for ciliogenesis translates into a signaling-pathway deficit.

    Evidence shRNA/siRNA knockdown with ciliogenesis quantification, SHH reporter assay, and patient fibroblast analysis

    PMID:34523780

    Open questions at the time
    • Whether SHH/WNT effects are solely secondary to cilium loss unresolved
    • Single lab
  5. 2024 Medium

    Extended KIAA0753 function to osteoblast differentiation, showing direct interactions with SHH/Gli2 and a role in stabilizing Gli2 against degradation under diabetic conditions.

    Evidence Co-IP with SHH/OCN/Gli2, shRNA knockdown and overexpression in MC3T3 osteoblasts, cilia length, ubiquitination and Hedgehog reporter assays

    PMID:39245790

    Open questions at the time
    • Direct vs. cilium-mediated effect on Gli2 stability not separated
    • Single cell system, single lab
  6. 2025 Medium

    Defined a post-translational control mechanism for OFIP, showing UFL1-mediated UFMylation limits its stability and governs centrosomal localization in a cell-type-specific manner.

    Evidence In vivo and in vitro UFL1-OFIP co-IP, UFMylation immunoblotting, RT-qPCR and centrosomal localization imaging in HeLa vs RPE1 cells

    PMID:40059580

    Open questions at the time
    • UFMylation site(s) on OFIP not mapped
    • Basis of HeLa vs RPE1 cell-type specificity unexplained
  7. 2025 Medium

    Resolved the spatial organization of KIAA0753/MNR at the distal centriole as part of the DISCO complex and identified C2CD3 as required to position it at future appendage sites.

    Evidence U-ExM, iterative U-ExM and in situ cryo-electron tomography with C2CD3 depletion (preprint)

    PMID:bio_10.1101_2025.06.17.660204

    Open questions at the time
    • Preprint, single lab
    • Direct C2CD3-MNR interface and stoichiometry of DISCO not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how KIAA0753 mechanistically couples distal-centriole assembly to Hedgehog signaling output and how its UFMylation, CEP120 recruitment, and DISCO assembly are integrated.
  • No structural model of the full DISCO complex
  • Regulatory hierarchy linking UFMylation, CEP120 recruitment, and signaling unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005815 microtubule organizing center 2 GO:0005929 cilium 2
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
C2CD3CEP120FOR20GLI2OFD1SHHUFL1
Complex memberships
DISCO complex (MNR/CEP90/OFD1)KIAA0753–OFD1–FOR20 ternary complex

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 KIAA0753/OFIP localizes to centrosomes and pericentriolar satellites in human cells and forms a ternary complex with OFD1 and FOR20; decreased expression of any component causes defective recruitment of the others onto centrosomes and satellites. An OFD-associated KIAA0753 mutant loses its capacity to interact with FOR20 and OFD1. KIAA0753/OFIP also possesses microtubule-stabilizing activity. Co-immunoprecipitation, immunofluorescence localization in RPE1 cells, siRNA knockdown with recruitment phenotype readout, microtubule stabilization assay, OFD mutant interaction analysis Human molecular genetics High 26643951
2017 Loss-of-function mutations in KIAA0753 cause defective ciliogenesis in patient fibroblasts, establishing KIAA0753 as required for primary cilia formation. Patient fibroblast analysis for ciliation defects following identification of compound heterozygous mutations by whole exome sequencing Human genetics Medium 28220259
2021 CEP120 directly recruits KIAA0753 to centrioles; loss of this interaction causes accumulation of granule neuron progenitors (GNPs) in the germinal zone and impairs neuronal differentiation in the developing cerebellum. JS-associated CEP120 mutants that cannot recruit KIAA0753 fail to rescue these defects, whereas wild-type CEP120 does. Co-immunoprecipitation (CEP120–KIAA0753 interaction), in vivo cerebellar GNP depletion assays, rescue experiments with wild-type vs. JS-mutant CEP120, cell cycle exit quantification Genes & development High 34711653
2021 Ablation of KIAA0753 in vitro blocks primary ciliogenesis and suppresses Sonic Hedgehog (SHH) pathway activity; patient fibroblasts carrying biallelic KIAA0753 variants show a deficit in primary ciliation and blunted SHH and WNT signaling responses. shRNA/siRNA knockdown of KIAA0753 in cell lines with ciliogenesis quantification, SHH pathway reporter assay, patient fibroblast functional analysis American journal of medical genetics. Part A Medium 34523780
2024 KIAA0753 promotes osteoblast differentiation by directly interacting with SHH, OCN, and Gli2, thereby activating the Hedgehog signaling pathway and mitigating ubiquitination-mediated degradation of Gli2 under high-glucose (diabetic) conditions. Knockdown shortens primary cilia; overexpression rescues ciliation and Hedgehog pathway activity. Co-immunoprecipitation (KIAA0753 with SHH, OCN, Gli2), shRNA knockdown and overexpression in MC3T3 osteoblasts, primary cilia length measurement, ubiquitination assay, Hedgehog pathway reporter Journal of cellular and molecular medicine Medium 39245790
2025 OFIP/KIAA0753 undergoes UFMylation catalyzed by the E3 ligase UFL1; UFL1 interacts with OFIP both in vivo and in vitro and promotes its UFMylation. This modification inhibits OFIP protein stability and is required for proper centrosomal localization of OFIP in HeLa cells, but not in RPE1 cells, indicating cell-type-specific regulation. Co-immunoprecipitation (UFL1–OFIP), immunoblotting for UFMylation, RT-qPCR, immunofluorescence microscopy for centrosomal localization Journal of clinical laboratory analysis Medium 40059580
2025 MNR/KIAA0753 is part of the DISCO complex (MNR/CEP90/OFD1) at the distal centriole; C2CD3 depletion disrupts recruitment of the DISCO complex via direct interaction with MNR, and C2CD3 is required to position MNR/DISCO at future appendage sites on the centriole. Ultrastructure Expansion Microscopy (U-ExM), iterative U-ExM, in situ cryo-electron tomography, C2CD3 depletion with DISCO complex localization readout bioRxivpreprint Medium bio_10.1101_2025.06.17.660204

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 OFIP/KIAA0753 forms a complex with OFD1 and FOR20 at pericentriolar satellites and centrosomes and is mutated in one individual with oral-facial-digital syndrome. Human molecular genetics 39 26643951
2017 Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency. Human genetics 29 28220259
2017 Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies. Scientific reports 27 29138412
2001 Hypoxia in fetal lambs: a study with (1)H-MNR spectroscopy of cerebrospinal fluid. Pediatric research 17 11328955
1978 Comparison of the haplotypes of the major histocompatibility complex in the rat. III. Two difficult haplotypes: H-1h (Ag-B12) in the HW strain and Ag-B13 (H-1m) in the MNR/N strain. Journal of immunogenetics 16 366023
2021 CEP120-mediated KIAA0753 recruitment onto centrioles is required for timely neuronal differentiation and germinal zone exit in the developing cerebellum. Genes & development 7 34711653
2019 A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy. European journal of medical genetics 7 31816441
2021 Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies. American journal of medical genetics. Part A 5 34523780
2021 The Membrane-Bound Notch Regulator Mnr Supports Notch Cleavage and Signaling Activity in Drosophila melanogaster. Biomolecules 4 34827670
2025 UFMylation Modulates OFIP Stability and Centrosomal Localization. Journal of clinical laboratory analysis 3 40059580
2024 KIAA0753 enhances osteoblast differentiation suppressed by diabetes. Journal of cellular and molecular medicine 2 39245790
2002 Is the Mnr locus of Triticeae species the same as the Ndh and Dia loci? TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik 0 12582652

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