Nuclear transport: Barring faulty exports

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Nuclear retention of unspliced mRNAs in yeast is mediated by perinuclear Mlp1.

Reporting in Cell, Vincent Galy et al. have begun to unravel the molecular mechanisms underlying a process that has been largely inaccessible to experimentation — nuclear retention of unspliced mRNAs.

Building on previous work on the yeast structural proteins Mlp1 and Mlp2, the authors made a surprising discovery: Mlp1 and Mlp2 are distributed asymmetrically in the nuclear envelope, adjacent to chromatin. This prompted them to investigate what processes might take advantage of this unusual Mlp distribution.

Galy et al. found that inactivation of the splicing factor Prp18 was synthetically lethal with MLP1 deletion. Deleting MLP1 or MLP2 had no detectable effect on splicing; instead, mlp1 and prp18 mutant strains both 'leaked' intron-containing mRNAs (MLP2 deletion had no such effect), and combining both mutations was additive.

But how does Mlp1 function to retain RNAs in the nucleus? Galy et al. found that, on Mlp1 overexpression, intranuclear Mlp1 clusters trap specifically intron-containing mRNAs, and identified SF1 as an RNA-dependent Mlp1-binding partner. SF1 is known to bind specifically to the branchpoint region of intron-containing RNAs, so the RNA-dependent interaction between SF1 and Mlp1 demonstrates a physical link between Mlp1 and unspliced mRNAs. Further data indicates that the 5' splice site mediates Mlp1-dependent retention.

Finally — building on evidence that the nucleoporin Nup60 docks Mlp1 and Mlp2 into position, and that its deletion mislocalizes them both — nup60-dependent release of Mlp1 was shown to result in more severe (but less specific) pre-mRNA leakage and a splicing defect, which indicates that Nup60 is also involved in pre-mRNA retention.

So, Galy et al. have shown, for the first time, that splicing and pre-mRNA retention are functionally distinct processes, and propose that in its asymmetric distribution "...Mlp1 implements a quality control step prior to export, physically retaining faulty pre-mRNAs".

Natalie Wilson

References

Galy, V. et al. Nuclear retention of unspliced mRNAs in yeast is mediated by perinuclear Mlp1. Cell 116, 63–73 (2004) | PubMed |