Activation-dependent TRAF3 exon 8 alternative splicing is controlled by CELF2 and hnRNP C binding to an upstream intronic element

Astrid Solveig Schultz, Marco Preussner, Mario Bunse, Rotem Karni, Florian Heyd*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Cell-type-specific and inducible alternative splicing has a fundamental impact on regulating gene expression and cellular function in a variety of settings, including activation and differentiation. We have recently shown that activationinduced skipping of TRAF3 exon 8 activates noncanonical NF-κB signaling upon T cell stimulation, but the regulatory basis for this splicing event remains unknown. Here we identify cis- and trans-regulatory elements rendering this splicing switch activation dependent and cell type specific. The cis-acting element is located 340 to 440 nucleotides upstream of the regulated exon and acts in a distance-dependent manner, since altering the location reduces its activity. A small interfering RNA screen, followed by cross-link immunoprecipitation and mutational analyses, identified CELF2 and hnRNP C as trans-acting factors that directly bind the regulatory sequence and together mediate increased exon skipping in activated T cells. CELF2 expression levels correlate with TRAF3 exon skipping in several model systems, suggesting that CELF2 is the decisive factor, with hnRNP C being necessary but not sufficient. These data suggest an interplay between CELF2 and hnRNP C as the mechanistic basis for activation-dependent alternative splicing of TRAF3 exon 8 and additional exons and uncover an intronic splicing silencer whose full activity depends on the precise location more than 300 nucleotides upstream of the regulated exon.

Original languageAmerican English
Article numbere00488-16
JournalMolecular and Cellular Biology
Volume37
Issue number7
DOIs
StatePublished - 2017

Bibliographical note

Publisher Copyright:
© 2017 American Society for Microbiology. All Rights Reserved.

Keywords

  • RNA binding proteins
  • RNA splicing

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