The exon junction complex undergoes a compositional switch that alters mRNP structure and nonsense-mediated mRNA decay activity

TL;DR

This study reveals a dynamic compositional switch in the exon junction complex (EJC) that changes mRNP structure and modulates nonsense-mediated mRNA decay, highlighting distinct roles of RNPS1 and CASC3 in post-transcriptional regulation.

Contribution

It uncovers the structural and compositional remodeling of EJC during mRNP maturation and its differential impact on NMD activity, a novel insight into post-transcriptional gene regulation.

Findings

EJC starts as an RNPS1-containing complex and switches to a CASC3-containing complex in the cytoplasm.

RNPS1 is broadly important for NMD, while CASC3 affects only specific mRNAs.

The compositional switch to CASC3 slows down NMD, indicating functional regulation.

Abstract

The exon junction complex (EJC) deposited upstream of mRNA exon junctions shapes structure, composition and fate of spliced mRNA ribonucleoprotein particles (mRNPs). To achieve this, the EJC core nucleates assembly of a dynamic shell of peripheral proteins that function in diverse post-transcriptional processes. To illuminate consequences of EJC composition change, we purified EJCs from human cells via peripheral proteins RNPS1 and CASC3. We show that EJC originates as an SR-rich mega-dalton sized RNP that contains RNPS1 but lacks CASC3. After mRNP export to the cytoplasm and before translation, the EJC undergoes a remarkable compositional and structural remodeling into an SR-devoid monomeric complex that contains CASC3. Surprisingly, RNPS1 is important for nonsense-mediated mRNA decay (NMD) in general whereas CASC3 is needed for NMD of only select mRNAs. The promotion of switch to CASC3-EJC slows down NMD. Overall, the EJC compositional switch dramatically alters mRNP structure and specifies two distinct phases of EJC-dependent NMD.