Antiviral Immune Response as a Trigger of FUS Proteinopathy in Amyotrophic Lateral Sclerosis

• Published in: Cell reports (Cambridge) Vol. 29; no. 13; pp. 4496 - 4508.e4
• Main Authors: Shelkovnikova, Tatyana A., An, Haiyan, Skelt, Lucy, Tregoning, John S., Humphreys, Ian R., Buchman, Vladimir L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.12.2019; Cell Press; Elsevier
• Subjects: Active Transport, Cell Nucleus - genetics; Active Transport, Cell Nucleus - immunology; ALS; amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - immunology; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Amyotrophic Lateral Sclerosis - virology; antiviral response; Cell Cycle Proteins - genetics; Cell Cycle Proteins - immunology; Cell Line; Cytoplasmic Granules - genetics; Cytoplasmic Granules - immunology; Cytoplasmic Granules - virology; dopamine; dsRNA; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - immunology; FUS; FUS proteinopathy; fused in sarcoma; Gene Expression Regulation; Host-Pathogen Interactions - drug effects; Host-Pathogen Interactions - genetics; Host-Pathogen Interactions - immunology; Humans; Inclusion Bodies - genetics; Inclusion Bodies - immunology; Inclusion Bodies - virology; Interferon Type I - genetics; Interferon Type I - immunology; Male; Membrane Transport Proteins - genetics; Membrane Transport Proteins - immunology; Motor Neurons - immunology; Motor Neurons - metabolism; Motor Neurons - virology; Neuroglia - immunology; Neuroglia - metabolism; Neuroglia - virology; nucleocytoplasmic transport; Nucleocytoplasmic Transport Proteins - genetics; Nucleocytoplasmic Transport Proteins - immunology; optineurin; Poly I-C - pharmacology; Primary Cell Culture; Protein Aggregates - genetics; Protein Aggregates - immunology; Respiratory Syncytial Virus; Respiratory Syncytial Viruses - immunology; Respiratory Syncytial Viruses - pathogenicity; RNA granule; RNA Stability; RNA, Messenger - genetics; RNA, Messenger - immunology; RNA-Binding Protein FUS - genetics; RNA-Binding Protein FUS - immunology; Spinal Cord - immunology; Spinal Cord - metabolism; Spinal Cord - pathology; Spinal Cord - virology; stress granule; dsRNA; Respiratory Syncytial Virus; FUS; stress granule; RNA granule; ALS; FUS proteinopathy; amyotrophic lateral sclerosis; fused in sarcoma; antiviral response; optineurin; nucleocytoplasmic transport; dopamine
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.11.094

Mutations in the FUS gene cause familial amyotrophic lateral sclerosis (ALS-FUS). In ALS-FUS, FUS-positive inclusions are detected in the cytoplasm of neurons and glia, a condition known as FUS proteinopathy. Mutant FUS incorporates into stress granules (SGs) and can spontaneously form cytoplasmic RNA granules in cultured cells. However, it is unclear what can trigger the persistence of mutant FUS assemblies and lead to inclusion formation. Using CRISPR/Cas9 cell lines and patient fibroblasts, we find that the viral mimic dsRNA poly(I:C) or a SG-inducing virus causes the sustained presence of mutant FUS assemblies. These assemblies sequester the autophagy receptor optineurin and nucleocytoplasmic transport factors. Furthermore, an integral component of the antiviral immune response, type I interferon, promotes FUS protein accumulation by increasing FUS mRNA stability. Finally, mutant FUS-expressing cells are hypersensitive to dsRNA toxicity. Our data suggest that the antiviral immune response is a plausible second hit for FUS proteinopathy. [Display omitted] •Viral infection or its mimic induce large, persistent assemblies of mutant FUS•These assemblies sequester optineurin and nucleocytoplasmic transport factors•Mutant FUS-expressing cells are hypersensitive to virus-induced toxicity•Type I interferon induced by viral infections promotes accumulation of FUS protein Amyotrophic lateral sclerosis caused by mutations in the FUS gene is characterized by cytoplasmic FUS pathology (FUS proteinopathy). Shelkovnikova et al. find that the antiviral immune response promotes FUS protein accumulation and its coalescence into persistent cytoplasmic assemblies. Viral infection can serve as a trigger of FUS proteinopathy in ALS.