An ATP-gated molecular switch orchestrates human messenger RNA export
Article Date: 06 November 2025
Article URL: https://www.nature.com/articles/s41586-025-09832-z
Article Image: (none provided)
Summary
This Nature manuscript (preview) reveals the mechanistic basis of human mRNA export. The authors show that the ATPase DDX39 (also known as UAP56) functions as an ATP-gated molecular switch that controls an mRNA-binding cycle. This cycle directs mRNPs from nucleoplasmic TREX complexes to NPC-anchored TREX-2 complexes, enabling docking at the nuclear pore complex and release for export. The conclusions rest on complementary biochemical and structural data and propose a conserved, general pathway for mRNA export in eukaryotes.
Key Points
- DDX39/UAP56 is identified as a central ATP-gated switch regulating human mRNA export.
- DDX39’s ATP-bound and ADP-bound states control its mRNA-binding cycle and interactions with export machinery.
- The switch promotes remodelling of TREX-bound mRNPs and their transfer to TREX-2 at the nuclear pore complex (NPC).
- Biochemical and structural experiments support a stepwise pathway: TREX remodelling → NPC docking → release and initiation of export.
- The mechanism is proposed as general and evolutionarily conserved across eukaryotes.
- The work integrates in vitro reconstitution, structural biology and functional assays to map the pathway components and transitions.
Content summary
The study dissects subsequent events after mRNP assembly, which were previously poorly understood. Using purified components and structural analysis the team shows how DDX39’s nucleotide state gates mRNA binding and release, enabling directional handover of mRNPs from TREX to TREX-2 complexes anchored at the NPC. This handover explains how mRNPs become export-competent, dock at the pore and are released to commence translocation into the cytoplasm. The authors present a coherent model supported by biochemical remodelling assays and structural snapshots.
Context and relevance
mRNA export is a fundamental step in gene expression; defects cause disease and affect many cellular processes. By providing a molecular mechanism for the TREX→TREX-2 transition and NPC handover, this work fills a major gap between transcription-coupled mRNP assembly and nuclear pore transit. The findings will interest researchers studying RNA biology, nucleocytoplasmic transport, and related disease mechanisms, and may inform future therapeutic strategies targeting RNA export defects.
Why should I read this?
Short and blunt: if you care about how messages get out of the nucleus this paper nails down the missing switch. It explains who does the handing-off, how ATP flips the switch, and why that matters for export. Great if you want a mechanistic frame for lots of downstream biology — and it saves you hours of digging through fragmentary reports.