Abstract: Alternative splicing is controlled by differential binding of trans-acting RNA binding proteins (RBPs) to cis-regulatory pre-mRNA elements. How pre-mRNA secondary structure affects recognition by RBPs and determines alternative exon usage is poorly understood. The MALT1 paracaspase is a key component of signaling pathways that mediate innate and adaptive immune responses. Alternative splicing of MALT1 exon7 is critical for controlling optimal T cell activation. Here, we demonstrate that MALT1 pre-mRNA splicing depends on RNA structural elements that shield the splice sites of the alternatively spliced exon7. The RBPs hnRNP U and hnRNP L bind comparably and competitively to identical stem-loop RNA structures flanking the 5’ and 3’ splice sites of MALT1 exon7. While hnRNP U stabilizes RNA stem-loop conformations that maintain exon7 skipping, hnRNP L destabilizes these RNA elements to facilitate recruitment of the essential splicing factor U2AF2 to promote exon7 inclusion. This work represents a paradigm for the control of splice site selection by differential RBP binding and modulation of pre-mRNA structure.
Monday, January 10, 2022 - 4:00pm
Technical University of Munich