Why Is Hu Where? Shuttling of Early-Response-Gene Messenger RNA Subsets

Post-transcriptional regulation of gene expression involves multiple checkpoints at which decisions are made concerning the fate of each messenger RNA species. Primary transcripts assemble into multicomponent ribonucleoprotein complexes during pre-mRNA processing in the spliceosome, are transported out of the nucleus, and are either stored, degraded, or translated in the cytoplasm. Determining the outcome of this process for each individual mRNA species is complicated by the heterogeneity of the messenger ribonucleoprotein (mRNP) population, which contains various-size transcripts and diverse combinations of attached proteins. Although investigators have not yet devised methods to separate and characterize distinct cellular mRNPs, nature appears to distinguish each mRNP by using inherent signals in the RNAs and/or in the proteins in the mRNP complexes and tracking each mRNA to an appropriate functional outcome. For example, mRNAs may contain recognition sequences that can serve as "zip codes" for tracking or localization whereas in other cases, proteins attached to the mRNPs contain localization signals that allow their movement out of, or into, the nucleus. In a previous issue of the Proceedings, Fan and Steitz define a novel nuclear shuttling sequence in the Hu RNA-binding protein HuR, which may transport a specific subset of cellular mRNAs containing AU-rich elements (ARE) from the nucleus to the cytoplasm. They term this signal the "HNS" for HuR nuclear-cytoplasmic shuttling sequence because it contains both nuclear export and nuclear localization elements. This is particularly interesting because the ARE- containing mRNAs encode a functionally important subset of early-response gene (ERG) or immediate-early gene products, including protooncoproteins and cytokines.