RanBP2/Nup358 Potentiates the Translation of a Subset of mRNAs Encoding Secretory Proteins

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Abstract
In higher eukaryotes, most mRNAs that encode secreted or membrane-bound proteins contain elements that promote an alternative mRNA nuclear export (ALREX) pathway. Here we report that ALREX-promoting elements also potentiate translation in the presence of upstream nuclear factors. These RNA elements interact directly with, and likely co-evolved with, the zinc finger repeats of RanBP2/Nup358, which is present on the cytoplasmic face of the nuclear pore. Finally we show that RanBP2/Nup358 is not only required for the stimulation of translation by ALREX-promoting elements, but is also required for the efficient global synthesis of proteins targeted to the endoplasmic reticulum (ER) and likely the mitochondria. Thus upon the completion of export, mRNAs containing ALREX-elements likely interact with RanBP2/Nup358, and this step is required for the efficient translation of these mRNAs in the cytoplasm. ALREX-elements thus act as nucleotide platforms to coordinate various steps of post-transcriptional regulation for the majority of mRNAs that encode secreted proteins. About one-fifth of the protein-coding genes in the human genome code for secreted and/or membrane-bound proteins. In the nucleus these genes are transcribed into messenger RNAs (mRNAs), which are then exported to the cytoplasm. These mRNAs are then transported to the surface of the endoplasmic reticulum where they are translated into proteins destined for the secretory pathway. Most of these mRNAs contain signal sequence coding regions (SSCRs), which code for short hydrophobic polypeptides that target the newly synthesized proteins for translocation across the endoplasmic reticulum membrane. Previously, we found that many SSCRs also act as RNA elements that promote the efficient nuclear export of mRNAs. Here we present evidence that upon the completion of nuclear export, SSCR-containing mRNAs interact with RanBP2/Nup358, a large protein found on the cytoplasmic face of the nuclear pore. This interaction is mediated by direct binding between the SSCR and zinc finger repeats found within RanBP2/Nup358, and is ultimately required for the efficient translation of SSCR-containing mRNAs into secretory and/or membrane-bound proteins. Our work demonstrates that SSCRs act as nucleotide platforms that recruit various factors to the mRNA throughout its life to regulate distinct events, such as nuclear export and translation.

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