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

被引：25

作者：

Jones, Alisha N. ^{[1
,2
]}

Grass, Carina ^{[3
]}

Meininger, Isabel ^{[3
]}

Geerlof, Arie ^{[1
]}

Klostermann, Melina ^{[4
,5
]}

Zarnack, Kathi ^{[4
,5
]}

Krappmann, Daniel ^{[3
]}

Sattler, Michael ^{[1
,2
]}

机构：

[1] Helmholtz Zentrum Munchen, Inst Struct Biol, Mol Targets & Therapeut Ctr, D-85764 Munich, Germany

[2] Tech Univ Munich, Bavarian NMR Ctr, Dept Chem, D-85748 Munich, Germany

[3] Helmholtz Zentrum Munchen, Inst Mol Toxicol & Pharmacol, Res Unit Cellular Signal Integrat, Mol Targets & Therapeut Ctr, D-85764 Munich, Germany

[4] Goethe Univ Frankfurt, Buchmann Inst Mol Life Sci BMLS, Max Laue Str 15, D-60438 Frankfurt, Germany

[5] Goethe Univ Frankfurt, Fac Biol Sci, Max Von Laue Str 15, D-60438 Frankfurt, Germany

来源：

SCIENCE ADVANCES | 2022年 / 8卷 / 31期

关键词：

SELECTIVE 2'-HYDROXYL ACYLATION; SECONDARY STRUCTURE; NMR-SPECTROSCOPY; BINDING; MECHANISMS; MOTIF; SITE; RECOGNITION; ACTIVATION; INSIGHTS;

D O I：

10.1126/sciadv.abp9153

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：14

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[21] Application of phase-modulated CLEAN chemical EXchange spectroscopy (CLEANEX-PM) to detect water-protein proton exchange and intermolecular NOEs [J].