Affinage

CEP19

Centrosomal protein of 19 kDa · UniProt Q96LK0

Length
163 aa
Mass
19.2 kDa
Annotated
2026-06-09
14 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

CEP19 is a centrosomal and ciliary-base scaffold protein that initiates intraflagellar transport (IFT) by coupling the distal centriole to the small GTPase RABL2 (PMID:28625565, PMID:28428259). Recruited to the mother centriole through binding FGFR1OP (FOP) within the CEP350/FOP module, CEP19 captures GTP-bound RABL2, which in turn engages and releases the IFT-B holocomplex via the IFT74-IFT81 heterodimer in a mutually exclusive, GTP-dependent manner, thereby licensing entry of IFT trains into the cilium (PMID:28625565, PMID:28428259). The IFT81/74 coiled-coil acts as an unconventional GAP that accelerates RABL2 GTP hydrolysis, driving RABL2 dissociation from anterograde IFT trains after engagement (PMID:37606072). Assembly of the CEP350/FOP/CEP19 module at the distal centriole is positioned downstream of the distal centriolar hub proteins Talpid3, C2CD3, and OFD1 during organelle maturation (PMID:30258116). Through this RABL2-IFT-B axis, CEP19 is required for proper ciliary trafficking of G-protein-coupled receptors: its loss mislocalizes GPR161 and HTR6 (PMID:30578315), and CEP19-dependent RABL2 recruitment is needed for BBSome-mediated export of ciliary GPCRs including GPR161 and Smoothened (PMID:36074075). Homozygous loss-of-function mutation of CEP19 causes morbid obesity, hyperphagia, glucose intolerance, and insulin resistance in humans and mice, linking this ciliary signaling function to energy balance (PMID:24268657).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2013 High

    Established that CEP19 is a centrosomal/ciliary protein with a physiological role, by tying its loss to a defined metabolic disease phenotype.

    Evidence Homozygosity mapping and Sanger sequencing in humans plus Cep19 knockout mouse phenotyping and immunofluorescence localization

    PMID:24268657

    Open questions at the time
    • Did not define the molecular partners or biochemical activity of CEP19
    • Mechanism linking ciliary function to energy balance unresolved
  2. 2017 High

    Defined the core molecular axis, showing CEP19 is recruited by the CEP350/FOP module and captures GTP-bound RABL2 to license IFT-B train entry into the cilium.

    Evidence Affinity-purification mass spectrometry, reciprocal Co-IP, siRNA knockdown, Chlamydomonas RABL2 disruption, rescue and biochemical reconstitution across two independent labs

    PMID:28428259 PMID:28625565

    Open questions at the time
    • Did not resolve how RABL2 is subsequently released from IFT trains
    • Structural basis of the mutually exclusive CEP19/IFT74-IFT81 binding not determined
  3. 2018 Medium

    Placed CEP19 module assembly within centriole maturation, ordering its recruitment downstream of distal centriolar hub proteins.

    Evidence Genetic loss-of-function (siRNA/knockout) of Talpid3, C2CD3, OFD1 with immunofluorescence readout of CEP19 module assembly

    PMID:30258116

    Open questions at the time
    • Single lab
    • Direct versus indirect regulation of CEP19 recruitment not distinguished
  4. 2019 Medium

    Connected the CEP19 axis to ciliary GPCR targeting by showing its loss mislocalizes specific receptors.

    Evidence siRNA knockdown of CEP19 with immunofluorescence quantification of GPR161 and HTR6 ciliary localization

    PMID:30578315

    Open questions at the time
    • Single lall single-method phenotype
    • Whether the defect reflects import, retention, or export not distinguished here
  5. 2022 Medium

    Extended the role to BBSome-mediated export, showing CEP19-dependent RABL2 entry is required for ciliary GPCR removal.

    Evidence GTP-locked RABL2(Q80L) expression, IFT27 knockout, CEP19 depletion, immunofluorescence for ciliary cargo accumulation

    PMID:36074075

    Open questions at the time
    • Single lab
    • Direct biochemical link between CEP19/RABL2 and the BBSome not established
  6. 2023 High

    Resolved the cycle's termination step by identifying IFT81/74 as the GAP that drives RABL2 GTP hydrolysis and release from IFT trains.

    Evidence In vitro reconstitution of RabL2 with CEP19 or IFT proteins, GTPase activity assays, IFT81/74 coiled-coil mutagenesis, and structural modelling validated in vitro and in cellulo

    PMID:37606072

    Open questions at the time
    • High-resolution structure of the CEP19-RABL2 complex not reported
    • Nucleotide exchange factor activity for RABL2 loading not fully defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the molecular CEP19-RABL2-IFT-B trafficking cycle mechanistically produces the organismal hyperphagia and obesity phenotype remains unresolved.
  • No in vivo link between specific mislocalized GPCRs and the metabolic phenotype
  • Tissue-specific requirements for CEP19 not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005815 microtubule organizing center 3 GO:0005929 cilium 3
Pathway
R-HSA-9609507 Protein localization 3 R-HSA-162582 Signal Transduction 2 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
CEP350FGFR1OPIFT74IFT81RABL2RABL2B
Complex memberships
CEP350/FOP/CEP19 module

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 CEP19 is recruited to the ciliary base by the centriolar CEP350/FOP complex, where it specifically captures GTP-bound RABL2B (activated via its intrinsic nucleotide exchange). Activated RABL2B then captures and releases the IFT-B holocomplex from the pool of pre-docked IFT-B complexes to initiate ciliary entry of IFT trains. Affinity-purification mass spectrometry, Co-IP, rescue experiments, biochemical reconstitution of interactions Developmental cell High 28625565
2017 RABL2 is recruited to the mother centriole/basal body in a CEP19-dependent manner, and CEP19 itself is recruited to the centriole via its binding to FGFR1OP (FOP). RABL2 binds CEP19 and the IFT74-IFT81 heterodimer of the IFT-B complex in a mutually exclusive, GTP-dependent manner. Co-immunoprecipitation, siRNA knockdown, Chlamydomonas RABL2 gene disruption, localization by immunofluorescence Molecular biology of the cell High 28428259
2013 CEP19 localizes to the centrosome and primary cilia. Homozygous loss-of-function mutation (nonsense) in CEP19 causes morbid obesity, hyperphagia, glucose intolerance, and insulin resistance in humans and mice, establishing a functional role for CEP19 in energy balance via ciliary signaling. Homozygosity mapping, Sanger sequencing, Cep19 knockout mouse phenotyping (weight, food intake, glucose tolerance tests), immunofluorescence localization American journal of human genetics High 24268657
2018 Talpid3, C2CD3, and OFD1 differentially regulate the assembly of the CEP350/FOP/CEP19 module at the distal centriole, placing CEP19 recruitment downstream of these distal centriolar hub proteins during organelle maturation. Genetic loss-of-function (siRNA/knockout) combined with immunofluorescence to measure CEP19 module assembly at the centriole Nature communications Medium 30258116
2019 Ablation of CEP19 causes mis-localization of ciliary GPCRs GPR161 and HTR6, placing CEP19 (via its interaction with RABL2 and IFT-B) in the pathway required for ciliary GPCR targeting. siRNA knockdown of CEP19 followed by immunofluorescence quantification of ciliary GPCR localization Journal of cell science Medium 30578315
2022 GTP-locked RABL2 (Q80L) enters cilia in a manner dependent on the basal body protein CEP19, phenocopying IFT27 knockout by causing accumulation of BBSome components within cilia and suppressing export of ciliary GPCRs GPR161 and Smoothened, indicating that CEP19-dependent RABL2 recruitment at the ciliary base is required for BBSome-mediated GPCR export. Expression of GTP-locked RABL2(Q80L), IFT27 knockout, CEP19 knockout/depletion, immunofluorescence for ciliary cargo accumulation Molecular biology of the cell Medium 36074075
2023 A reconstituted pentameric IFT complex containing IFT81/74 acts as an unconventional GAP (GTPase-activating protein) for RabL2 (RABL2), enhancing its GTP hydrolysis rate. CEP19 interacts with RabL2 at the basal body upstream of IFT engagement, and structural models validated in vitro and in cellulo show how RabL2 is incorporated into and then dissociates from the IFT complex after GTP hydrolysis. In vitro reconstitution and purification of RabL2 with CEP19 or IFT proteins, GTPase activity assay, structural modelling validated in vitro and in cellulo, mutagenesis of IFT81/74 coiled-coil The EMBO journal High 37606072

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 The CEP19-RABL2 GTPase Complex Binds IFT-B to Initiate Intraflagellar Transport at the Ciliary Base. Developmental cell 94 28625565
2017 RABL2 interacts with the intraflagellar transport-B complex and CEP19 and participates in ciliary assembly. Molecular biology of the cell 76 28428259
2013 Morbid obesity resulting from inactivation of the ciliary protein CEP19 in humans and mice. American journal of human genetics 55 24268657
2018 A distal centriolar protein network controls organelle maturation and asymmetry. Nature communications 41 30258116
2019 RABL2 positively controls localization of GPCRs in mammalian primary cilia. Journal of cell science 25 30578315
2017 Homozygous mutation in CEP19, a gene mutated in morbid obesity, in Bardet-Biedl syndrome with predominant postaxial polydactyly. Journal of medical genetics 25 29127258
2020 Analysis of the "centrosome-ome" identifies MCPH1 deletion as a cause of centrosome amplification in human cancer. Scientific reports 14 32681070
2022 Genetic and epigenetic interplay allows rapid transgenerational adaptation to metal pollution in zebrafish. Environmental epigenetics 11 36474803
2023 The IFT81-IFT74 complex acts as an unconventional RabL2 GTPase-activating protein during intraflagellar transport. The EMBO journal 9 37606072
2022 CEP19-RABL2-IFT-B axis controls BBSome-mediated ciliary GPCR export. Molecular biology of the cell 9 36074075
2021 Comparative transcriptome provides insights into the selection adaptation between wild and farmed foxes. Ecology and evolution 7 34646484
2023 Comparison of symmetrical and asymmetrical cleavage 2-cell embryos of porcine by Smart-seq2. Theriogenology 4 37540954
2023 Severe Early-Onset Obesity and Diabetic Ketoacidosis due to a Novel Homozygous c.169C>T p.Arg57* Variant in CEP19 Gene. Molecular syndromology 1 38585545
2017 Gating Ciliary Transport. Developmental cell 0 28697332

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