Abstract
BackgroundType I interferons (IFN-I) are key responders to central nervous system infection and injury and are also increased in common neurodegenerative diseases. Their effects are primarily mediated via transcriptional regulation of several hundred interferon-regulated genes. In addition, IFN-I activate several kinases including members of the MAPK and PI3K families. Yet, how changes to the global protein phosphoproteome contribute to the cellular response to IFN-I is unknown.MethodsThe cerebral phosphoproteome of mice with brain-targeted chronic production of the IFN-I, IFN-α, was obtained. Changes in phosphorylation were analyzed by ontology and pathway analysis and kinase enrichment predictions. These were verified by phenotypic analysis, immunohistochemistry and immunoblots. In addition, primary murine microglia and astrocytes, the brain's primary IFN-I-responding cells, were acutely treated with IFN-α and the global phosphoproteome was similarly analyzed.ResultsWe identified widespread protein phosphorylation as a novel mechanism by which IFN-I mediate their effects. In our mouse model for IFN-I-induced neurodegeneration, protein phosphorylation, rather than the proteome, aligned with the clinical hallmarks and pathological outcome, including impaired development, motor dysfunction and seizures. In vitro experiments revealed extensive and rapid IFN-I-induced protein phosphorylation in microglia and astrocytes. 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.ConclusionsOur 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.
Highlights
Type I interferons (IFN-I) are key responders to central nervous system infection and injury and are increased in common neurodegenerative diseases
A total of 5,616 proteins were detected with one protein less abundant and 70 proteins more abundant (|z-score|≥ 1.96 and |fold change|≥ 1.5) in the proteome of the cerebellum of GFAP-IFNα mice (GIFN39) mice compared with WT mice (Fig. 1A and Additional file 1: Tables S1 and S2)
Using Ingenuity Pathway Analysis (IPA), enriched canonical pathways consisting of the proteins with elevated abundance in the cerebellum of GIFN39 mice were associated with interferon signaling, antigen presentation, acute phase response and interestingly, but less significant, SLE signaling (Fig. 1B)
Summary
Type I interferons (IFN-I) are key responders to central nervous system infection and injury and are increased in common neurodegenerative diseases. Their effects are primarily mediated via transcriptional regulation of several hundred interferon-regulated genes. IFN-I-mediated CNS inflammation and neurodegeneration are known as “cerebral type I interferonopathies” [5, 6]. They include genetic diseases (e.g., Aicardi–Goutières Syndrome, AGS), chronic and congenital infections (e.g., HIV, toxoplasma, and cytomegalovirus) and autoinflammatory disorders (e.g., neurological manifestations of systemic lupus erythematosus, SLE) [6,7,8]. The mechanisms of how IFN-I drive neurological diseases are unclear, making causal treatment difficult
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