Structural Superimposition

Abstact

Eukaryotic genomes generate a plethora of polyadenylated (pA(+)) RNAs(1,2), which are packaged into ribonucleoprotein particles (RNPs). To ensure faithful gene expression, functional pA(+) RNPs, including protein-coding RNPs, are exported to the cytoplasm, whereas transcripts within non-functional pA(+) RNPs are degraded in the nucleus(1-4). How cells distinguish these opposing fates remains unknown. The DExD-box ATPase UAP56 (also known as DDX39B) is a central component of functional pA(+) RNPs, and promotes their docking to the nuclear pore complex-anchored TREX-2(5,6), which triggers transcript release from UAP56 to facilitate export(7). Here we reveal that the poly(A) tail exosome targeting (PAXT) connection(8) binds a TREX-2-like module, which releases pA(+) RNAs from UAP56 for decay by the nuclear exosome. The core of this module consists of a LENG8-PCID2-SEM1 trimer, which we show is structurally and biochemically equivalent to the central GANP-PCID2-SEM1 trimer of TREX-2. Mutagenesis and transcriptomic data demonstrate that the nuclear fate of pA(+) RNPs is governed by the contending actions of nucleoplasmic PAXT and nuclear pore complex-associated TREX-2, which interpret RNA-bound UAP56 as a signal for RNA decay or export, respectively. As RNA targets of PAXT are generally short and intron-poor, we propose an overall model for pA(+) RNP fate determination whereby the distinct sub-nuclear localizations of PAXT and TREX-2 govern the degradation of short non-functional pA(+) RNAs while allowing export of their longer and functional counterparts.