Key result
Down-regulation of hnRNP U decreased the caspase-9a/9b mRNA ratio, demonstrating that hnRNP U competes with hnRNP L to enhance caspase-9 splicing, which is blocked by the AKT pathway.
This study identifies hnRNP U as a novel enhancer of pro-apoptotic caspase-9a splicing, which is antagonized by AKT-dependent phosphorylation of hnRNP L.
Animal data position hnRNP U as apoptosis regulator; leaves open human cardiovascular relevance and therapeutic targeting.
Caspase-9 has two splice variants, pro-apoptotic caspase-9a and anti-apoptotic caspase-9b, which are regulated by RNA trans-factors associated with exon 3 of caspase-9 pre-mRNA (C9/E3). In this study, we identified hnRNP U as an RNA trans-factor associated with C9/E3. Down-regulation of hnRNP U led to a decrease in the caspase-9a/9b mRNA ratio, demonstrating a novel enhancing function. Importantly, hnRNP U bound specifically to C9/E3 at an RNA cis-element previously reported as the binding site for the splicing repressor, hnRNP L. Phosphorylated hnRNP L interfered with hnRNP U binding to C9/E3, and our results demonstrate the importance of the phosphoinositide 3-kinase/AKT pathway in modulating the association of hnRNP U to C9/E3. Taken together, these findings show that hnRNP U competes with hnRNP L for binding to C9/E3 to enhance the inclusion of the four-exon cassette, and this splice-enhancing function is blocked by the AKT pathway via phosphorylation of hnRNP L.
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Vu et al. (2013) studied this question. hnRNP U down-regulation was evaluated on caspase-9a/9b mRNA ratio and binding to C9/E3. Down-regulation of hnRNP U decreased the caspase-9a/9b mRNA ratio, demonstrating that hnRNP U competes with hnRNP L to enhance caspase-9 splicing, which is blocked by the AKT pathway.
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