Neurochondrin promotes U5 snRNP maturation by regulating AAR2 release from PRPF8

Pre-mRNA splicing is orchestrated by the spliceosome, a dynamic and highly regulated ribonucleoprotein complex composed of five small nuclear ribonucleoproteins (snRNPs). Despite extensive studies, the biogenesis of snRNPs remains incompletely understood. Here, we identify neurochondrin (NCDN) as a critical regulator of U5 snRNP biogenesis. NCDN associates with PRPF8-AAR2-EFTUD2 complex in the cytoplasm and is essential for the proper progression of this assembly intermediate toward mature U5 snRNP formation. Loss of NCDN causes the accumulation of this intermediate, resulting in a decreased level of mature U5 snRNP. Spliceosome dysregulation often leads to alternative splicing abnormalities implicated in cancer. Indeed, NCDN deficiency suppresses tumor cell proliferation and induces apoptosis, while high NCDN expression promotes tumor cell growth and correlates with poor survival in glioblastoma patients. Transcriptome analyses reveal that loss of NCDN causes widespread alternative splicing defects and changes in gene expression. Collectively, these results establish NCDN as an essential factor for U5 snRNP assembly and spliceosome function, and highlight its potential as a therapeutic target in glioma with elevated NCDN expression.