Nitric oxide drives proteomic diversity through alternative splicing

Redox signaling by nitric oxide (NO) is estimated to control a large part of the global proteome via S-nitrosylation (SNO-modification). Here, we report that RNA-binding proteins (RBPs) represent the most significantly enriched class of S-nitrosylation targets, with broad coverage of spliceosomal factors. We demonstrate that NO regulates alternative splicing (AS) and that S-nitrosylation of PTBP1, a central regulator of AS, can massively shift and contextually alter gene expression while further enriching the transcriptome for SNO sites. PTBP1 S-nitrosylation changes RNA-binding domain conformation, RNA motif recognition, protein-RNA and protein-protein interactions, and intracellular trafficking to impact pathways for viral infection and neurodegeneration. Levels of SNO-PTBP1 are reduced in mouse and human Alzheimer's disease brains and correlate with adverse clinical outcomes. Overall, SNO-RBPs are characterized by conservation across diverse lineages and SNO sites and provide a blueprint for redox regulation of both transcriptome and proteome in physiology and disease.