title: TDP-43 regulates global translational yield by splicing of exon junction complex component SKAR.
abstract: TDP-43 is linked to neurodegenerative diseases including frontotemporal dementia and amyotrophic lateral sclerosis. Mostly localized in the nucleus, TDP-43 acts in conjunction with other ribonucleoproteins as a splicing co-factor. Several RNA targets of TDP-43 have been identified so far, but its role(s) in pathogenesis remains unclear. Using Affymetrix exon arrays, we have screened for the first time for splicing events upon TDP-43 knockdown. We found alternative splicing of the ribosomal S6 kinase 1 (S6K1) Aly/REF-like target (SKAR) upon TDP-43 knockdown in non-neuronal and neuronal cell lines. Alternative SKAR splicing depended on the first RNA recognition motif (RRM1) of TDP-43 and on 5'-GA-3' and 5'-UG-3' repeats within the SKAR pre-mRNA. SKAR is a component of the exon junction complex, which recruits S6K1, thereby facilitating the pioneer round of translation and promoting cell growth. Indeed, we found that expression of the alternatively spliced SKAR enhanced S6K1-dependent signaling pathways and the translational yield of a splice-dependent reporter. Consistent with this, TDP-43 knockdown also increased translational yield and significantly increased cell size. This indicates a novel mechanism of deregulated translational control upon TDP-43 deficiency, which might contribute to pathogenesis of the protein aggregation diseases frontotemporal dementia and amyotrophic lateral sclerosis.
authors: Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases, University of Tübingen, 72076 Tübingen, Germany. Fiesel.Fabienne@mayo.edu
authors: Fabienne C
authors: FC
authors: Fiesel
authors: Stephanie S
authors: SS
authors: Weber
authors: Jochen
authors: J
authors: Supper
authors: Andreas
authors: A
authors: Zell
authors: Philipp J
authors: PJ
authors: Kahle
mesh_terms: D017398:Alternative Splicing; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D005091:Exons; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012091:Repetitive Sequences, Nucleic Acid; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C495327:POLDIP3 protein, human; D020033:Protein Isoforms; D016601:RNA-Binding Proteins