Fused in sarcoma (FUS) is a multifunctional protein involved in transcriptional control, pre-mRNA processing, RNA transport and translation. The domain structure of FUS reflects its functions in gene regulation and its ability to interact with other proteins, RNA and DNA. By use of a recombinant fragment of FUS in pull-down experiments followed by mass spectrometry analysis we have identified a novel interaction between the FUS N-terminal and the cytolinker plectin. An in situ proximity ligation assay confirmed that FUS-plectin interactions take place in the cytoplasm of cells. Furthermore, plectin deficient cells showed an altered subcellular localization of FUS and a deregulated expression of mRNAs bound to FUS. Our results show that plectin is important for normal FUS localization and function. Mutations involving FUS are causative factors in sarcomas and leukemias and also hereditary forms of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Plectin deficiency causes epidermolysis bullosa, a disease involving the skin and neuromuscular system. The novel FUS-plectin interaction offers new perspectives for understanding the role of FUS and plectin mutations in the pathogenesis of these diseases.Highlights
▸ A pull-down screen was performed to identify novel interaction partners of FUS/TLS. ▸ An interaction with plectin was identified and shown to occur in the cytoplasm. ▸ FUS localization and function is compromised in cells lacking plectin expression. ▸ Plectin may act as a scaffold for FUS and facilitate FUS mediated RNA transport.