Functional diversification of the cephalopod proteome by RNA-editing

Coleoid cephalopods exhibit the highest levels of ADAR-mediated RNA editing of any known animal, yet the functional consequences of most recoding events remain largely unknown. We integrate proteomics with biochemical and cellular assays to characterize thousands of recoding events across the Doryteuthis pealeii proteome. Using quantitative and functional mass spectrometry, we show that RNA edit-driven recoding reshapes the cellular proteome to alter protein stability, subcellular localization, post-translational modifications, and enzymatic activity. -Recoding can regulate post-translational modifications through their creation or ablation, and this has direct effects on protein function and protein-protein interactions. Recoding of the E3 ligase MARCHF5 drives widespread changes in substrate ubiquitylation and perturbs mitochondrial homeostasis, illustrating how RNA editing can influence organelle function. These data provide the first proteome-scale view of how extensive RNA recoding diversifies protein function in coleoid cephalopods and offers a new framework for understanding how RNA-level plasticity shapes protein function and cellular physiology.