Omics · study · 2026
CRL5-WSB2 Inactivation Drives BIM/NOXA-Mediated Neuronal Apoptosis in Luo-Agrawal Syndrome
Listed in NCBI GEO
Biallelic mutations in WSB2 have recently been linked to Luo-Agrawal syndrome, a newly recognized neurodevelopmental disorder characterized by severe microcephaly and brain hypoplasia; however, the precise molecular mechanisms driving this disease remain elusive.
Description
Here, we identify the multi-subunit Cullin-RING E3 ubiquitin ligase 5 (CRL5)-WSB2 complex as an indispensable post-translational clearance system and developmental safeguard during human corticogenesis.
Genetic disruption of WSB2 or other key components of the CRL5 complex leads to a dramatic, post-translational co-accumulation of the pro-apoptotic factors BIM and NOXA, lower the apoptotic threshold in both mouse and human cell models. Mechanistically, patient-derived C-terminal mutations (R391Q and K413RfsTer19) within the SOCS box domain disrupt the structural assembly of the CRL5-WSB2 holoenzyme by abolishing its interaction with CUL5 and Elongin B/C. Consequently, these variants function as inactive or dominant-negative receptors that physically trap BIM and NOXA but fail to deliver them to the catalytic core for polyubiquitination and proteasomal degradation.
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To model the pathogenesis of Luo-Agrawal syndrome in human neural tissues, we engineered homozygous WSB2-knockout human induced pluripotent stem cells (iPSCs) and differentiated them into three-dimensional (3D) cerebral organoids. WSB2 inactivation triggers a severe growth and morphogenetic defect in the developing cortical structures, driven by massive, spontaneous activation of the caspase cascade and widespread neuronal apoptosis.
Strikingly, lentiviral-mediated shRNA knockdown of either BIM or NOXA successfully mitigates active caspase signaling and fully rescues the apoptotic microcephaly phenotype in the WSB2-deficient cortical tissues. Taken together, our findings unveil a crucial CRL5-WSB2–BIM/NOXA regulatory axis that restricts death-inducing factors to ensure human neurodevelopment, establishing that holoenzyme inactivation drives the pathological apoptotic clearance of nascent neural populations in Luo-Agrawal syndrome.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE345nnn/GSE345497 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE345497 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1520237 ncbi.nlm.nih.gov/bioproject/PRJNA1520237 ↗
project · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Mus musculus
- From keywords
- Life Sciences
- Inferred from text
- Disease 75%
Provenance · 1 source records, 8 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE345497 | 12 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[disease].local:disease:disease | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[organism].NCBITaxon:10090 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |