Alternative splicing of MALT1 controls signalling and activation of CD4(+) T cells.

Isabel Meininger,Andrea C Eitelhuber,Andreas Gewies,Jan Kranich,Arianna Bertossi,Jürgen Ruland,Desheng Hu,Thomas Brocker,Daniel Krappmann,Torben Gehring,Marc Schmidt-Supprian,Florian Heyd,Thomas Seeholzer,Andrea Oeckinghaus,Richard A Griesbach,Ute Greczmiel,Vigo Heissmeyer

doi:10.1038/ncomms11292

Abstract

MALT1 channels proximal T-cell receptor (TCR) signalling to downstream signalling pathways. With MALT1A and MALT1B two conserved splice variants exist and we demonstrate here that MALT1 alternative splicing supports optimal T-cell activation. Inclusion of exon7 in MALT1A facilitates the recruitment of TRAF6, which augments MALT1 scaffolding function, but not protease activity. Naive CD4+ T cells express almost exclusively MALT1B and MALT1A expression is induced by TCR stimulation. We identify hnRNP U as a suppressor of exon7 inclusion. Whereas selective depletion of MALT1A impairs T-cell signalling and activation, downregulation of hnRNP U enhances MALT1A expression and T-cell activation. Thus, TCR-induced alternative splicing augments MALT1 scaffolding to enhance downstream signalling and to promote optimal T-cell activation.

Highlights

MALT1 channels proximal T-cell receptor (TCR) signalling to downstream signalling pathways
Lower MALT1A expression and induction of MALT1A after T-cell stimulation was observed in human CD4 þ T cells from peripheral blood
We identified the RNA-binding protein heterogeneous nuclear ribonucleoprotein U (hnRNP U) as a negative regulator of exon[7] inclusion in human Jurkat and murine primary T cells and we show that MALT1A upregulation enhances T-cell signalling and activation

Summary

Introduction

MALT1 channels proximal T-cell receptor (TCR) signalling to downstream signalling pathways. Inclusion of exon[7] in MALT1A facilitates the recruitment of TRAF6, which augments MALT1 scaffolding function, but not protease activity. TCR-induced alternative splicing augments MALT1 scaffolding to enhance downstream signalling and to promote optimal T-cell activation. MALT1 (mucosaassociated lymphoid tissue protein 1) bridges TCR/CD28 co-engagement to cellular downstream signalling pathways to promote T-cell activation and effector functions[1,2]. Alternative splicing can act on multiple layers ranging from cell surface receptors, cytokines, signalling proteins to transcription factors, and thereby constitutes an essential regulatory mechanism for T-cell function[15,16]. We identify heterogeneous nuclear ribonucleoprotein U (hnRNP U; SAF-A/SP120) as a factor that controls alternative MALT1 splicing and demonstrate that TCR-induced splicing of MALT1 increases relative MALT1A expression, which augments MALT1 scaffolding function and fosters activation of CD4 þ T cells

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Conclusion