Translational control by the RNA-binding protein CSDE1 : Insights into a stimulatory role in translation elongation

RNA-binding proteins are potent regulators of post-transcriptional gene expression. Among the repertoire of RNAs bound by a particular RNA-binding protein, networks of co-ordinately regulated RNAs, or ‘regulons’, are functionally related and their regulation in concert acts to drive cellular processes. In melanoma, the RNA-binding protein CSDE1 is highly upregulated. In this context, CSDE1 regulates the translation of mRNA targets in multiple regulons in a direction that is consistent with oncogenic progression, whereby, tumour- suppressors, such as PTEN, are downregulated and pro-metastatic factors, for example, the key epithelial-to-mesenchymal transition proteins, VIM and RAC1, are upregulated. Ribosome profiling studies indicate that CSDE1 enhances the translation of VIM and RAC1 at the level of translation elongation. Such a stimulatory role for an RNA-binding protein in translation elongation may represent a novel mechanism of translational regulation. Here, we seek to elucidate the protein partners of CSDE1 in inducing this unusual stimulatory effect on translation elongation, and to explore the relationship of CSDE1 to the translational machinery. We confirm that CSDE1 promotes the translation of RAC1 mRNA at the level of elongation, and further highlight a rapid adaptation of melanoma cells to CSDE1 depletion. We demonstrate extensive contact of CSDE1 with the translational machinery. CSDE1 is a ribosome-associated protein, interacting with the small ribosomal subunit, and is further observed to co-sediment with translating polysomes. Amongst 38 high-confidence CSDE1- interacting proteins that we identify in melanoma are 16 ribosomal proteins and a further 11 members of the ribo-interactome. Moreover, we show that CSDE1 associates to tRNAs in a manner dependent on both isodecoder and isoacceptor identity, and within these subgroups disparate patterns of CSDE1 affinity to the tRNA structure may be observed. The data lead us to propose a model whereby the stimulatory effect of CSDE1 on translation elongation may be underpinned by the binding of CSDE1 to both its target mRNAs and to tRNAs, thereby concentrating tRNAs towards the translating ribosome. Wurth, L., Papasaikas, P., Olmeda, D., Bley, N., Calvo, G.T., Guerrero, S., Cerezo- Wallis, D., Martinez-Useros, J., Garcia-Fernandez, M., Huttelmaier, S., et al. (2016). UNR/CSDE1 Drives a Post-transcriptional Program to Promote Melanoma Invasion and Metastasis. Cancer Cell 30, 694–707. Wurth, L., Papasaikas, P., Olmeda, D., Bley, N., Calvo, G.T., Guerrero, S., Cerezo- Wallis, D., Martinez-Useros, J., Garcia-Fernandez, M., Huttelmaier, S., et al. (2019). UNR/CSDE1 Drives a Post-transcriptional Program to Promote Melanoma Invasion and Metastasis. Cancer Cell 36, 337.