Phosphorylation of CSDE1 drives ribosome interactions with implications for cancer malignancy

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 in melanoma, where it promotes invasion and metastasis, whereas it behaves as a tumour suppressor in squamous cell carcinoma, a tumor derived from keratinocytes. 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 and keratinocytes, as well as in cells of different tumorigenic potential. Combining Nanopore sequencing with two-dimensional gel electrophoresis and proteomics, we identify one major CSDE1 isoform expressed in melanoma cells and patient samples and find that CSDE1 phosphorylation and interactions with ribosomes represent an early event in cellular transformation, correlating with changes in the subcellular localization of CSDE1. Our data show that CSDE1 phosphorylation promotes de novo interactions of CSDE1 with ribosomes, uncovering a specific vulnerability of melanoma cells that might be harnessed for therapeutic intervention.