title: Minor intron splicing is regulated by FUS and affected by ALS-associated FUS mutants.
abstract: Fused in sarcoma (FUS) is a ubiquitously expressed RNA-binding protein proposed to function in various RNA metabolic pathways, including transcription regulation, pre-mRNA splicing, RNA transport and microRNA processing. Mutations in the FUS gene were identified in patients with amyotrophic lateral sclerosis (ALS), but the pathomechanisms by which these mutations cause ALS are not known. Here, we show that FUS interacts with the minor spliceosome constituent U11 snRNP, binds preferentially to minor introns and directly regulates their removal. Furthermore, a FUS knockout in neuroblastoma cells strongly disturbs the splicing of minor intron-containing mRNAs, among them mRNAs required for action potential transmission and for functional spinal motor units. Moreover, an ALS-associated FUS mutant that forms cytoplasmic aggregates inhibits splicing of minor introns by trapping U11 and U12 snRNAs in these aggregates. Collectively, our findings suggest a possible pathomechanism for ALS in which mutated FUS inhibits correct splicing of minor introns in mRNAs encoding proteins required for motor neuron survival.
authors.affiliation: Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Reber
authors.affiliation: Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland.
authors.forename: Jolanda
authors.initials: J
authors.lastname: Stettler
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy IFOM-FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Filosa
authors.affiliation: Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: Martino
authors.initials: M
authors.lastname: Colombo
authors.affiliation: Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Jutzi
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
authors.forename: Silvia C
authors.initials: SC
authors.lastname: Lenzken
authors.affiliation: Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schweingruber
authors.affiliation: Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland.
authors.forename: Rémy
authors.initials: R
authors.lastname: Bruggmann
authors.affiliation: IFOM-FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Bachi
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
authors.forename: Silvia Ml
authors.initials: SM
authors.lastname: Barabino
authors.affiliation: Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland marc.ruepp@dcb.unibe.ch oliver.muehlemann@dcb.unibe.ch.
authors.forename: Oliver
authors.identifier: 0000-0003-0657-1368
authors.initials: O
authors.lastname: Mühlemann
authors.affiliation: Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland marc.ruepp@dcb.unibe.ch oliver.muehlemann@dcb.unibe.ch.
authors.forename: Marc-David
authors.identifier: 0000-0003-3264-9800
authors.initials: MD
authors.lastname: Ruepp
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D002460:Cell Line; D006801:Humans; D007438:Introns; D050505:Mutant Proteins / Q000235:genetics* / Q000378:metabolism*; D012326:RNA Splicing; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism*
chemical_list: C000599550:FUS protein, human; D050505:Mutant Proteins; D034702:RNA-Binding Protein FUS
keywords: FUS; amyotrophic lateral sclerosis; minor intron splicing