Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 37, Issue 7, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00488-16
Keywords
RNA binding proteins; RNA splicing
Categories
Funding
- Emmy-Noether fellowship of the Deutsche Forschungsgemeinschaft [He5398/3]
- Fritz Thyssen Foundation [Az.10.12.1.158]
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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-kappa B 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.
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