Minor intron splicing is regulated by FUS and affected by ALS‐associated FUS mutants

Stefan Reber, Jolanda Stettler, Giuseppe Filosa, Martino Colombo, Daniel Jutzi, Silvia C Lenzken, Christoph Schweingruber, Rémy Bruggmann, Angela Bachi, Silvia Ml Barabino, Oliver Mühlemann, Marc‐David Ruepp

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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.
Original languageEnglish
Pages (from-to)1504-1521
Number of pages18
JournalThe EMBO journal
Issue number14
Early online date1 Jun 2016
Publication statusPublished - 15 Jul 2016


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