TDP-43 regulates global translational yield by splicing of exon junction complex component SKAR

Fabienne Fiesel, Stephanie S. Weber, Jochen Supper, Andreas Zell, Philipp J. Kahle

Research output: Contribution to journalArticle

50 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2668-2682
Number of pages15
JournalNucleic acids research
Volume40
Issue number6
DOIs
StatePublished - Mar 1 2012

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Ribosomal Protein S6 Kinases
Exons
Ribonucleoproteins
RNA Precursors
Alternative Splicing
Cell Size
Neurodegenerative Diseases
RNA
Cell Line
Growth
Proteins
Frontotemporal Dementia With Motor Neuron Disease

ASJC Scopus subject areas

  • Genetics

Cite this

TDP-43 regulates global translational yield by splicing of exon junction complex component SKAR. / Fiesel, Fabienne; Weber, Stephanie S.; Supper, Jochen; Zell, Andreas; Kahle, Philipp J.

In: Nucleic acids research, Vol. 40, No. 6, 01.03.2012, p. 2668-2682.

Research output: Contribution to journalArticle

Fiesel, Fabienne ; Weber, Stephanie S. ; Supper, Jochen ; Zell, Andreas ; Kahle, Philipp J. / TDP-43 regulates global translational yield by splicing of exon junction complex component SKAR. In: Nucleic acids research. 2012 ; Vol. 40, No. 6. pp. 2668-2682.
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