A novel phosphoproteomic landscape evoked in response to type I interferon in the brain and in glial cells

Type I interferons (IFN-I) are key responders to central nervous system infection and injury. They mediate their effects primarily via transcriptional regulation of several hundred interferon-regulated genes. Using a mouse model for IFN-I-induced neurodegeneration, we identified widespread protein phosphorylation as a new mechanism by which IFN-I mediate their effects. Protein phosphorylation aligned with the clinical hallmarks and pathological outcome, including impaired development, motor dysfunction and seizures. <em>In vitro</em> experiments revealed extensive and rapid IFN-I-induced protein phosphorylation in microglia and astrocytes, the brain’s primary IFN-I-responding cells. Response to acute IFN-I stimulation was independent of gene expression and mediated by a small number of kinase families. The changes in the phosphoproteome affected a diverse range of cellular processes and functional analysis suggested that this response induced an immediate reactive state and prepared cells for subsequent transcriptional responses. Our studies reveal a hitherto unappreciated role for changes in the protein phosphorylation landscape in cellular responses to IFN-I and thus provide insights for novel diagnostic and therapeutic strategies for neurological diseases caused by IFN-I.