Proteomic study identifies Aurora-A–mediated regulation of alternative splicing through multiple splicing factors
Arun Prasath Damodaran, Olivia Gavard, Jean‐Philippe Gagné, Malgorzata Ewa Rogalska, Amit K. Behera, Estefanía Mancini, Giulia Bertolin, Thibault Courthéoux, Bandana Kumari, Justine Cailloce, Agnès Méreau, Guy G. Poirier, Juan Valcárcel, Thomas Gonatopoulos-Pournatzis, Erwan Watrin, Claude Prigent
Abstract
The cell cycle regulator Aurora-A kinase presents an attractive target for cancer therapies, though its inhibition is also associated with toxic side effects. To gain a more nuanced understanding of Aurora-A function, we applied shotgun proteomics to identify 407 specific protein partners, including several splicing factors. Supporting a role in alternative splicing, we found that Aurora-A localizes to nuclear speckles, the storehouse of splicing proteins. Aurora-A interacts with and phosphorylates splicing factors both in vitro and in vivo, suggesting that it regulates alternative splicing by modulating the activity of these splicing factors. Consistently, Aurora-A inhibition significantly impacts the alternative splicing of 505 genes, with RNA motif analysis revealing an enrichment for Aurora-A interacting splicing factors. Additionally, we observed a significant positive correlation between the splicing events regulated by Aurora-A and those modulated by its interacting splicing factors. An interesting example is represented by CLK1 exon 4, which appears to be regulated by Aurora-A through SRSF3. Collectively, our findings highlight a broad role of Aurora-A in the regulation of alternative splicing.