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

Sci Adv. 2022 Aug 5;8(31):eabp9153. doi: 10.1126/sciadv.abp9153. Epub 2022 Aug 3.

Abstract

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.

MeSH terms

  • Alternative Splicing
  • Binding Sites
  • Exons
  • Heterogeneous-Nuclear Ribonucleoprotein L* / genetics
  • Heterogeneous-Nuclear Ribonucleoprotein L* / metabolism
  • Heterogeneous-Nuclear Ribonucleoprotein U / genetics
  • Heterogeneous-Nuclear Ribonucleoprotein U / metabolism
  • Heterogeneous-Nuclear Ribonucleoproteins / genetics
  • Heterogeneous-Nuclear Ribonucleoproteins / metabolism
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / genetics
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / metabolism
  • RNA Precursors* / genetics
  • RNA Splice Sites
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism

Substances

  • Heterogeneous-Nuclear Ribonucleoprotein L
  • Heterogeneous-Nuclear Ribonucleoprotein U
  • Heterogeneous-Nuclear Ribonucleoproteins
  • RNA Precursors
  • RNA Splice Sites
  • RNA-Binding Proteins
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein