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

TY - JOUR

T1 - Minor intron splicing is regulated by FUS and affected by ALS‐associated FUS mutants

AU - Reber, Stefan

AU - Stettler, Jolanda

AU - Filosa, Giuseppe

AU - Colombo, Martino

AU - Jutzi, Daniel

AU - Lenzken, Silvia C

AU - Schweingruber, Christoph

AU - Bruggmann, Rémy

AU - Bachi, Angela

AU - Barabino, Silvia Ml

AU - Mühlemann, Oliver

AU - Ruepp, Marc‐David

PY - 2016/7/15

Y1 - 2016/7/15

N2 - 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.

AB - 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.

U2 - 10.15252/embj.201593791

DO - 10.15252/embj.201593791

M3 - Article

SN - 0261-4189

VL - 35

SP - 1504

EP - 1521

JO - The EMBO journal

JF - The EMBO journal

IS - 14

ER -