Modulation of pre-mRNA structure by hnRNP proteins regulates alternative splicing of MALT1

Alisha N Jones, Carina Graß, Isabel Meininger, Arie Geerlof, Melina Klostermann, Kathi Zarnack, Daniel Krappmann, Michael Sattler (2022 Aug 5) Modulation of pre-mRNA structure by hnRNP proteins regulates alternative splicing of MALT1.
Sci Adv 8(31):eabp9153. doi: 10.1126/sciadv.abp9153.

Abstract cited directly from the article:

Alternative splicing plays key roles for cell type–specific regulation of protein function. It is controlled by cis-regulatory RNA elements that are recognized by RNA binding proteins (RBPs). The MALT1 paracaspase is a key factor of signaling pathways that mediate innate and adaptive immune responses. Alternative splicing of MALT1 is critical for controlling optimal T cell activation. We demonstrate that MALT1 splicing depends on RNA structural elements that sequester the splice sites of the alternatively spliced exon7. The RBPs hnRNP U and hnRNP L bind competitively to stem-loop RNA structures that involve the 5′ and 3′ splice sites flanking exon7. While hnRNP U stabilizes RNA stem-loop conformations that maintain exon7 skipping, hnRNP L disrupts these RNA elements to facilitate recruitment of the essential splicing factor U2AF2, thereby promoting exon7 inclusion. Our data represent a paradigm for the control of splice site selection by differential RBP binding and modulation of pre-mRNA structure.