title: Subcellular localization and RNAs determine FUS architecture in different cellular compartments.
abstract: Mutations in Fused in sarcoma (FUS) gene cause a subset of familial amyotrophic lateral sclerosis (ALS), a fatal motor neuron degenerative disease. Wild-type FUS is largely localized in the nucleus, but mutant FUS accumulates in the cytoplasm and forms inclusions. It is unclear whether FUS depletion from the nucleus or FUS inclusions in the cytoplasm triggers motor neuron degeneration. In this study, we revealed that the nuclear and cytoplasmic FUS proteins form distinct local distribution patterns. The nuclear FUS forms oligomers and appears granular under confocal microscope. In contrast, the cytoplasmic FUS forms inclusions with no oligomers detected. These patterns are determined by the subcellular localization of FUS, regardless of wild-type or mutant protein. Moreover, mutant FUS remained or re-directed in the nucleus can oligomerize and behave similarly to the wild-type FUS protein. We further found that nuclear RNAs are critical to its oligomerization. Interestingly, the formation of cytoplasmic FUS inclusions is also dependent on RNA binding. Since the ALS mutations disrupt the nuclear localization sequence, mutant FUS is likely retained in the cytoplasm after translation and interacts with cytoplasmic RNAs. We therefore propose that local RNA molecules interacting with the FUS protein in different subcellular compartments play a fundamental role in determining FUS protein architecture and function.
authors.affiliation: Department of Molecular and Cellular Biochemistry.
authors.forename: Liuqing
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Molecular and Cellular Biochemistry.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Graduate Center for Toxicology, College of Medicine, University of Kentucky, 741 South Limestone Street, Lexington, KY 40536, USA.
authors.forename: Marisa
authors.initials: M
authors.lastname: Kamelgarn
authors.affiliation: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China and.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Niu
authors.affiliation: Department of Molecular and Cellular Biochemistry.
authors.forename: Jozsef
authors.initials: J
authors.lastname: Gal
authors.affiliation: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China and Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230027, China.
authors.forename: Weimin
authors.initials: W
authors.lastname: Gong
authors.affiliation: Department of Molecular and Cellular Biochemistry, Graduate Center for Toxicology, College of Medicine, University of Kentucky, 741 South Limestone Street, Lexington, KY 40536, USA, haining@uky.edu.
authors.forename: Haining
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D055503:Protein Multimerization; D021381:Protein Transport; D012313:RNA / Q000378:metabolism*; D034443:RNA Transport; D034702:RNA-Binding Protein FUS / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D061785:Transcription Initiation, Genetic
chemical_list: D002843:Chromatin; D034702:RNA-Binding Protein FUS; D012313:RNA