Proteomic study identifies Aurora-A-mediated regulation of alternative splicing through multiple splicing factors

Damodaran, Arun Prasath; Gavard, Olivia; Gagné, Jean-Philippe; Rogalska, Malgorzata; Behera, Amit K.; Mancini, Estefanía; Bertolin, Giulia; Courthéoux, Thibault; Kumari, Bandana; Cailloce, Justine; Méreau, Agnès; Poirier, Guy G.; Valcárcel, J. (Juan); Gonatopoulos-Pournatzis, Thomas; Watrin, Erwan; Prigent, Claude

doi:http://dx.doi.org/10.1016/j.jbc.2024.108000

Proteomic study identifies Aurora-A-mediated regulation of alternative splicing through multiple splicing factors

Citation

Damodaran AP, Gavard O, Gagné JP, Rogalska ME, Behera AK, Mancini E, et al. Proteomic study identifies Aurora-A-mediated regulation of alternative splicing through multiple splicing factors. J Biol Chem. 2024 Nov 17;301(1):108000. DOI: 10.1016/j.jbc.2024.108000

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.