Affinage

CWC27

Spliceosome-associated protein CWC27 homolog · UniProt Q6UX04

Length
472 aa
Mass
53.8 kDa
Annotated
2026-06-09
12 papers in source corpus 5 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CWC27 is a spliceosome-associated, cyclophilin-type protein that functions as a structural scaffold during early spliceosome maturation rather than as an active enzyme (PMID:32329775, PMID:25478830). Although it retains a cyclophilin-type PPIase domain, higher eukaryotic CWC27 has lost a crucial active-site residue, converting it from a functional prolyl isomerase into a proline-binding scaffold (PMID:25478830). CWC27 heterodimerizes with the splicing factor CWC22, and this building block serves as an intermediate landing platform that positions the EJC core component eIF4A3 on the Bact spliceosome; a CWC27 loop sterically clashes with the EJC subunit Y14, requiring CWC27 to vacate before conversion to the C complex and EJC deposition (PMID:32329775). Consistent with this role, loss of CWC27 produces widespread splicing changes including altered splice-site usage and intron retention, and CWC27 cooperates with CWC22 in splicing overlapping gene sets (PMID:34726245, PMID:32329775). In mice, complete Cwc27 knockout causes embryonic lethality while hypomorphic alleles produce isolated retinal degeneration accompanied by ER stress (CHOP activation), and AAV8-mediated CWC27 gene augmentation rescues photoreceptor morphology and function, establishing CWC27 loss-of-function as the direct cause of the retinal phenotype (PMID:34726245, PMID:28285769, PMID:37479075).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2014 High

    Established that CWC27, despite carrying a cyclophilin-type PPIase domain, is not a catalytically active prolyl isomerase in higher eukaryotes, reframing it as a proline-binding scaffold.

    Evidence Crystal structures of the human (2.0Å) and Chaetomium thermophilum (1.3Å) PPIase domains with comparative sequence analysis showing active-site residue loss

    PMID:25478830

    Open questions at the time
    • Does not define what CWC27 binds in place of catalysis
    • No spliceosomal context provided in this study
  2. 2017 Medium

    Defined the in vivo requirement for CWC27, showing it is essential for embryonic development and that graded loss produces a phenotypic spectrum culminating in isolated retinal degeneration.

    Evidence Cwc27 knockout and hypomorphic mouse models with retinal histology and ERG

    PMID:28285769

    Open questions at the time
    • Molecular mechanism of splicing defects not directly shown
    • Does not explain retina-specific vulnerability
  3. 2020 High

    Resolved the molecular function of CWC27, showing it heterodimerizes with CWC22 to form an intermediate landing platform for eIF4A3 on the Bact spliceosome and must leave before EJC deposition.

    Evidence 3Å crystal structure of CWC27/CWC22/eIF4A3 ternary complex, co-IP, comparison with spliceosome cryo-EM structures, and siRNA knockdown RNA-seq in RPE cells

    PMID:32329775

    Open questions at the time
    • Does not establish the timing/trigger of CWC27 release in vivo
    • Inflammatory pathway upregulation upon knockdown is an indirect inference
  4. 2022 High

    Connected CWC27's spliceosomal role to disease, demonstrating that its loss causes widespread splicing defects and downstream ER stress in the retina.

    Evidence Cwc27K338fs/K338fs mouse, bulk and single-cell RNA-seq, and CHOP immunostaining

    PMID:34726245

    Open questions at the time
    • Specific mis-spliced transcripts driving ER stress not pinpointed
    • Causal link between splicing defects and CHOP activation not directly tested
  5. 2023 Medium

    Demonstrated causality and therapeutic tractability by rescuing the photoreceptor phenotype through CWC27 gene replacement.

    Evidence AAV8-GRK-Cwc27-FLAG subretinal delivery in mutant mice with ERG, H&E histology, immunostaining

    PMID:37479075

    Open questions at the time
    • Single approach and single lab
    • Durability and effect on ER stress markers not reported

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved why a ubiquitously required splicing scaffold produces tissue-restricted (retinal) pathology and which specific splicing targets link CWC27 loss to ER stress and photoreceptor death.
  • No identified critical mis-spliced transcript in photoreceptors
  • Mechanism of retina-specific sensitivity unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-8953854 Metabolism of RNA 2
Partners
CWC22EIF4A3
Complex memberships
CWC27/CWC22 heterodimerspliceosome (Bact complex)

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 CWC27 forms a heterodimer with splicing factor CWC22, and the crystal structure of the CWC27/CWC22/eIF4A3 ternary complex was solved at 3Å resolution, revealing that the CWC27/CWC22 building block acts as an intermediate landing platform for the EJC core component eIF4A3 on the Bact spliceosome complex prior to its conversion into the C complex. A CWC27 loop was shown to clash sterically with EJC core subunit Y14 in the C complex, explaining why CWC27 must leave before EJC deposition. X-ray crystallography (3Å structure), co-immunoprecipitation, structural comparison with published spliceosome cryo-EM structures, siRNA knockdown with RNA-seq Nucleic acids research High 32329775
2014 CWC27 contains a cyclophilin-type PPIase domain. Crystal structures of the human CWC27 PPIase domain (2.0Å) and the Chaetomium thermophilum ortholog (1.3Å) were solved. Comparative sequence analysis revealed that higher eukaryotic CWC27 proteins have lost a crucial active-site residue present in lower eukaryotes, indicating the protein evolved from a functional prolyl isomerase to a proline-binding scaffold without catalytic PPIase activity. X-ray crystallography (2.0Å human, 1.3Å fungal), multiple sequence alignment, secondary-structure prediction across eukaryotes Acta crystallographica. Section D, Biological crystallography High 25478830
2022 Cwc27 functions as a splicing factor in vivo in the retina. In Cwc27K338fs/K338fs mutant mice, bulk RNA-seq and single-cell RNA-seq of the retina demonstrated widespread splicing pattern changes including alternative splice site usage and intron retention, as well as gene expression changes. CHOP staining indicated activation of ER stress as a downstream consequence of splicing defects, suggesting ER stress as a disease mechanism in CWC27-related retinal degeneration. Loss-of-function mouse model (Cwc27K338fs/K338fs), bulk RNA-seq, single-cell RNA-seq, CHOP immunostaining Human molecular genetics High 34726245
2017 Complete knockout of Cwc27 in mice causes significant embryonic lethality and severe phenotypes, while a partial loss-of-function allele recapitulates isolated retinal degeneration, establishing that CWC27 is essential for embryonic development and that graded loss of CWC27 function produces a spectrum of phenotypes. Cwc27 knockout and hypomorphic mouse models; phenotypic analysis including retinal histology and ERG American journal of human genetics Medium 28285769
2023 AAV8-mediated subretinal delivery of exogenous CWC27 (AAV8-GRK-Cwc27-FLAG) in Cwc27 mutant mice rescued retinal morphology and function, reducing photoreceptor (including cone cell) degeneration as assessed by ERG and histology, establishing that CWC27 loss-of-function is the direct cause of the photoreceptor degeneration phenotype. AAV8 gene augmentation therapy in Cwc27 mutant mice, ERG, H&E histology, immunostaining Experimental eye research Medium 37479075
2020 Knockdown of either CWC27 or CWC22 in immortalized retinal pigment epithelial cells affects numerous common genes, and the most upregulated genes upon knockdown encode inflammatory factors, suggesting CWC27 and CWC22 cooperate in splicing the same pathways and that CWC27 deficiency promotes an inflammatory response in retinal cells. siRNA knockdown of CWC27 or CWC22 in RPE cells followed by RNA-seq Nucleic acids research Medium 32329775

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 Circular RNA Cwc27 contributes to Alzheimer's disease pathogenesis by repressing Pur-α activity. Cell death and differentiation 90 34504314
2017 Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies. American journal of human genetics 65 28285769
2020 Structural and functional insights into CWC27/CWC22 heterodimer linking the exon junction complex to spliceosomes. Nucleic acids research 36 32329775
2014 Structure and evolution of the spliceosomal peptidyl-prolyl cis-trans isomerase Cwc27. Acta crystallographica. Section D, Biological crystallography 20 25478830
2022 Cwc27, associated with retinal degeneration, functions as a splicing factor in vivo. Human molecular genetics 14 34726245
2019 Expanding the clinical and molecular spectrum of the CWC27-related spliceosomopathy. Journal of human genetics 13 31481716
2023 Gene augmentation therapy to rescue degenerative photoreceptors in a Cwc27 mutant mouse model. Experimental eye research 4 37479075
2023 Further delineation of the CWC27-associated spliceosomeopathy: Case report and review of the literature. American journal of medical genetics. Part A 3 36718996
2022 Susceptibility Loci in SLC15A1, UGT1A3, and CWC27 Genes Associated with Bladder Cancer in the Northeast Chinese Population. BioMed research international 3 36124064
2024 A novel small deletion in CWC27 gene associated with CWC27-related spliceosomeopathy. Ophthalmic genetics 2 38956876
2025 Spatiotemporal expression of CWC27 spliceosome-associated protein (CWC27) in the developing mouse inner ear. Gene expression patterns : GEP 0 40774603
2023 Retinitis pigmentosa with or without skeletal abnormalities due to homozygous mutations in the CWC27 gene: A case report. Medicine 0 38134094

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