Affinage

CEP19

Centrosomal protein of 19 kDa · UniProt Q96LK0

Length
163 aa
Mass
19.2 kDa
Annotated
2026-04-28
14 papers in source corpus 7 papers cited in narrative 7 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CEP19 is a centrosomal and ciliary base protein that functions as a critical gating factor for intraflagellar transport (IFT) initiation by capturing GTP-bound RABL2 at the basal body. CEP19 is recruited to the distal centriole through the CEP350/FOP complex, and its binding to activated RABL2 enables RABL2 to engage and release the pre-docked IFT-B holocomplex via IFT74–IFT81, thereby licensing ciliary entry of IFT trains; after departure, the IFT81/74 coiled-coil acts as a GAP to hydrolyze RABL2-GTP and dissociate RABL2 from anterograde trains (PMID:28625565, PMID:28428259, PMID:37606072). This CEP19–RABL2–IFT-B axis also governs BBSome-mediated export of ciliary GPCRs such as GPR161, linking it to ciliary signaling homeostasis (PMID:30578315, PMID:36074075). Homozygous loss-of-function mutations in CEP19 cause morbid obesity with hyperphagia, glucose intolerance, and insulin resistance in both humans and mice (PMID:24268657).

Mechanistic history

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

    Before CEP19's molecular function was known, genetic evidence established that it is a centrosome/cilium-associated protein whose loss causes a morbid obesity ciliopathy, demonstrating a previously unrecognized link between this uncharacterized centriolar protein and systemic energy balance.

    Evidence Homozygosity mapping in a consanguineous family plus Cep19-knockout mouse with metabolic phenotyping and immunolocalization

    PMID:24268657

    Open questions at the time
    • Molecular mechanism by which CEP19 loss leads to obesity was unknown
    • No binding partners or pathway placement identified
  2. 2017 High

    Two concurrent studies revealed that CEP19 is recruited to the centriole by CEP350/FOP and functions as a receptor for GTP-bound RABL2 at the basal body, establishing the CEP19–RABL2–IFT-B axis as the mechanism for initiating IFT ciliary entry.

    Evidence AP-MS, reciprocal Co-IP, GTPase binding assays, RABL2 gene disruption in Chlamydomonas, mutant expression in human cells, fluorescence microscopy (two independent labs)

    PMID:28428259 PMID:28625565

    Open questions at the time
    • Structural basis for CEP19–RABL2 and RABL2–IFT-B interactions not resolved
    • Mechanism of RABL2 GTP hydrolysis and train dissociation unknown
    • Connection between IFT initiation defect and obesity phenotype not mechanistically established
  3. 2018 Medium

    Epistasis analysis placed the CEP350/FOP/CEP19 module downstream of Talpid3 and C2CD3 during centriole maturation, establishing the hierarchical assembly pathway that positions CEP19 at the distal centriole.

    Evidence RNAi knockdown with rescue experiments and fluorescence microscopy epistasis in human cells

    PMID:30258116

    Open questions at the time
    • Direct biochemical interactions between Talpid3/C2CD3 and CEP19 module not demonstrated
    • Whether this hierarchy operates identically in vivo remains untested
  4. 2019 Medium

    Functional studies showed that CEP19 loss causes mis-localization of ciliary GPCRs (GPR161), extending the CEP19–RABL2 pathway beyond IFT initiation to ciliary receptor trafficking.

    Evidence siRNA knockdown with GPCR ciliary localization assays in mammalian cells

    PMID:30578315

    Open questions at the time
    • Whether CEP19 affects GPCR export directly through BBSome regulation or indirectly via general IFT defects was unresolved
    • Range of affected ciliary cargoes not systematically surveyed
  5. 2022 Medium

    Demonstration that GTP-locked RABL2(Q80L) phenocopies IFT27-KO (BBSome accumulation, GPCR export failure) and enters cilia in a CEP19-dependent manner revealed that RABL2 and IFT25–IFT27 compete for the same IFT74–IFT81 binding site, mechanistically coupling IFT initiation to BBSome-mediated ciliary export.

    Evidence RABL2 GTP-locked mutant expression, IFT27-KO cells, Co-IP, functional ciliary export assays

    PMID:36074075

    Open questions at the time
    • GAP identity for RABL2 GTP hydrolysis on IFT trains was still unknown
    • Structural basis for mutual exclusivity of RABL2 and IFT25–IFT27 binding not resolved
  6. 2023 High

    Reconstitution of the pentameric IFT complex identified the IFT81/74 coiled-coil as an unconventional GAP for RABL2, explaining how RABL2 dissociates from anterograde IFT trains after CEP19-dependent loading at the ciliary base and completing the GTPase cycle model.

    Evidence In vitro reconstitution, GTPase activity assay, structural modeling, mutagenesis, cell-based functional validation

    PMID:37606072

    Open questions at the time
    • High-resolution atomic structure of the CEP19–RABL2 complex remains unavailable
    • How CEP19–RABL2 pathway defects mechanistically drive obesity (neuronal vs. systemic ciliary dysfunction) is unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The precise mechanism by which CEP19/RABL2/IFT-B pathway disruption leads to morbid obesity — whether through defective ciliary signaling in hypothalamic neurons, adipocytes, or other cell types — remains an open question.
  • Cell-type-specific contributions to the obesity phenotype are not delineated
  • Atomic-resolution structures for CEP19 and its complexes are lacking
  • Whether CEP19 has functions independent of RABL2 and IFT is unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Localization
GO:0005815 microtubule organizing center 4 GO:0005929 cilium 1
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 4 R-HSA-5653656 Vesicle-mediated transport 4
Partners
CEP350FGFR1OPIFT74IFT81RABL2B
Complex memberships
CEP350/FOP/CEP19

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 pre-docked IFT-B complexes, initiating ciliary entry of IFT. Affinity-purification/mass spectrometry, Co-IP, GTPase binding assays, functional cell-based assays Developmental Cell High 28625565
2017 CEP19 is recruited to the centriole via binding to FGFR1OP (FOP), and RABL2 recruitment to the mother centriole/basal body is dependent on CEP19. RABL2 binds CEP19 and the IFT74-IFT81 heterodimer in a mutually exclusive manner, and GTP-bound RABL2 interacts with the IFT-B complex via IFT74-IFT81. Co-immunoprecipitation, RABL2 gene disruption in Chlamydomonas, exogenous expression of RABL2 mutants in human cells, fluorescence microscopy Molecular biology of the cell High 28428259
2013 CEP19 localizes to the centrosome and primary cilia; homozygous loss-of-function in humans and mice causes morbid obesity, hyperphagia, glucose intolerance, and insulin resistance, establishing CEP19 as a ciliary protein required for energy balance regulation. Homozygosity mapping, sequencing, Cep19-knockout mouse model with metabolic phenotyping, immunolocalization American Journal of Human Genetics High 24268657
2018 The CEP350/FOP/CEP19 module at the distal centriole is regulated by Talpid3 and C2CD3; Talpid3, C2CD3, and OFD1 differentially control assembly of sub-distal appendages, the CEP350/FOP/CEP19 module, centriolar satellites, and actin networks during centriole maturation. RNAi knockdown, rescue experiments, fluorescence microscopy, epistasis analysis in human cells Nature Communications Medium 30258116
2019 Ablation of CEP19 leads to mis-localization of ciliary GPCRs (GPR161), placing CEP19 upstream of RABL2-mediated GPCR ciliary trafficking at the ciliary base. siRNA knockdown, fluorescence microscopy, GPCR localization assays in mammalian cells Journal of Cell Science Medium 30578315
2022 GTP-bound RABL2 and IFT25-IFT27 bind the IFT74-IFT81 dimer of IFT-B in a mutually exclusive manner. GTP-locked RABL2(Q80L) phenocopies IFT27-KO cells (BBSome accumulation in cilia, failure to export ciliary GPCRs), and RABL2(Q80L) enters cilia in a CEP19-dependent manner. RABL2 GTP-locked mutant expression, IFT27-KO cells, fluorescence microscopy, Co-IP, functional ciliary export assays Molecular biology of the cell Medium 36074075
2023 The IFT81/74 coiled-coil region acts as an unconventional GAP for RabL2, enhancing its GTP hydrolysis rate. CEP19 binds RabL2 at the basal body prior to IFT complex association; structural models for the RabL2-IFT complex were validated in vitro and in cellulo, explaining how RabL2 dissociates from anterograde IFT trains after departure from the ciliary base. In vitro reconstitution of pentameric IFT complex, GTPase activity assay, structural modeling, mutagenesis, functional cell-based validation 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 75 28428259
2013 Morbid obesity resulting from inactivation of the ciliary protein CEP19 in humans and mice. American journal of human genetics 52 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 24 29127258
2020 Analysis of the "centrosome-ome" identifies MCPH1 deletion as a cause of centrosome amplification in human cancer. Scientific reports 13 32681070
2022 Genetic and epigenetic interplay allows rapid transgenerational adaptation to metal pollution in zebrafish. Environmental epigenetics 10 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 6 34646484
2023 Comparison of symmetrical and asymmetrical cleavage 2-cell embryos of porcine by Smart-seq2. Theriogenology 3 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 0 38585545
2017 Gating Ciliary Transport. Developmental cell 0 28697332