Antiviral Immune Response as a Trigger of FUS Proteinopathy in Amyotrophic Lateral Sclerosis
31 Pages Posted: 14 Mar 2019 Sneak Peek Status: PublishedMore...
Mutations in the fused in sarcoma (FUS) gene cause a subset of familial amyotrophic lateral sclerosis cases (ALS-FUS). Mutant FUS mislocalises to the cytoplasm of neurons and glia, where it eventually becomes deposited in a form of insoluble inclusions, thus marking the onset of FUS proteinopathy. Mutant FUS has high affinity to cytoplasmic RNA granules stress granules (SGs), and can also spontaneously form small RNA granules, which grow under conditions of stress. It is believed that stress-induced mutant FUS assemblies may become precursors of pathological inclusions, however the nature of stress which acts as a trigger for FUS proteinopathy is still elusive. To address this, we characterised the ability of known SG-inducing stresses to cause sustained presence of mutant FUS-enriched cytoplasmic assemblies. Using CRISPR/Cas9 cell lines expressing endogenous mutant FUS, we found that single application of a viral infection mimetic compound, synthetic double-stranded (ds) RNA poly(I:C), is sufficient to cause formation of cytoplasmic FUS-containing assemblies which persist in cells for up to 48 hours. These FUS assemblies sequester the autophagy receptor optineurin and nucleocytoplasmic transport factors including FUS import receptor, Transportin 1. Moreover, mutant FUS expressing cells, including patient fibroblasts, are hypersensitive to dsRNA toxicity. Finally, we found that an integral component of the antiviral immune response, type I interferon, promotes FUS protein accumulation by increasing its mRNA stability. Our data suggest that antiviral immune response can expedite the onset and progression of FUS proteinopathy by promoting FUS protein accumulation and its coalescence into persistent cytoplasmic aggregates.
Keywords: fused in sarcoma (FUS), amyotrophic lateral sclerosis (ALS), stress granule, RNA granule, FUS proteinopathy, antiviral response, dsRNA, optineurin, nucleoplasmic transport
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