Context-dependent phosphorylation of CSDE1 drives interactions with ribosomes.

The RNA-binding protein CSDE1 is a key regulator of mRNA stability and translation in a broad spectrum of biological processes. We have previously shown that CSDE1 functions as an oncoprotein promoting invasion and metastasis in melanoma, whereas it behaves as a tumour suppressor promoting cellular senescence in squamous cell carcinoma. The reasons underlying these context-specific behaviours are unknown. To identify melanoma-specific vulnerabilities, we have compared CSDE1 protein isoforms and post-translational modifications in melanoma cells, keratinocytes, and melanocytic cells of different tumorigenic potential. By combining long-read Nanopore sequencing with two-dimensional gel electrophoresis and transcriptome analysis, we identify one major isoform expressed in melanoma cells and patient samples. This isoform is phosphorylated early during cellular transformation, correlating with changes in its subcellular localization. We provide extensive interactome analysis of mammalian CSDE1, showing increased interactions with ribosomes in melanoma cells compared to healthy melanocytes. Importantly, interactions of CSDE1 with the ribosome are promoted by CSDE1 phosphorylation. Our data uncover a specific feature of melanoma cells that could be harnessed for therapeutic intervention.