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CRL5-WSB2 Inactivation Drives BIM/NOXA-Mediated Neuronal Apoptosis in Luo-Agrawal Syndrome

ABSTRACT: 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. 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. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE345497 | GEO | 2026/09/10

REPOSITORIES: GEO

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Project description: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. 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. 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.

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CRL5-WSB2 Inactivation Drives BIM/NOXA-Mediated Neuronal Apoptosis in Luo-Agrawal Syndrome

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