The Double Lives of Shuttling mRNA Binding Proteins

Several other RNA binding proteins besides hnRNPs have been identified that not only function only in the nucleus but also regulate events in the cytoplasm. These include the transcription factors Bicoid and FRGY2, and the RNA splicing regulator SXL, which have all recently been shown to regulate translation (7xGray, N.K and Wickens, M. Annu. Rev. Cell Dev. Biol. 1998; 14: 399–458Crossref | PubMed | Scopus (412)See all References, 17xMatsumoto, K, Wassarman, K, and Wolffe, A.P. EMBO J. 1998; 17: 2107–2121Crossref | PubMed | Scopus (151)See all References and references therein). Our knowledge of these RNA binding proteins suggests that many of them first complex with pre-mRNAs in the nucleus to regulate their activities and then escort mature mRNAs out to the cytoplasm to further influence their behavior. However, this appealing scenario remains unproven. Even in the case of proteins known to shuttle between the nucleus and the cytoplasm, it is not known whether these RNA binding proteins actually direct (rather than follow) mRNAs to the cytoplasm. In fact, it is not even clear whether most shuttling RNA binding proteins are bound to RNA when they traverse the nuclear pore. Instead, many RNA binding proteins may travel to the cytoplasm alone. Another unanswered question is how shuttling RNA binding proteins reach the cytoplasm. Do most of them emigrate from the nucleus, or does a selected subset set up permanent residence at their place of origin in the cytoplasm?Despite these unanswered questions, the observation that many shuttling RNA binding proteins perform duties in both the nucleus and the cytoplasm suggests the following model (Figure 1Figure 1). In the nucleus, shuttling proteins promote the assembly of a proper mRNP (mRNA/protein) complex, permitting its export to the cytoplasm. After emerging from the nucleus, these RNA binding proteins then direct the assembly or reorganization of the RNP complex to help dictate the specific outcome appropriate for a given mRNA. According to this model, the particular shuttling proteins bound to the mRNA determines where the mRNA will be localized in the cytoplasm, its rate of translation, and its rate of decay. It is possible that these shuttling proteins regulate these posttranscriptional events by interacting with microtubules, ribosomes, and degradosomes, either directly or via adaptor proteins.Figure 1Model for How Shuttling mRNA Binding Proteins Regulate Events in Both the Nucleus and the CytoplasmPABP, poly(A) binding protein; eIF4F, eukaryotic initiation factor 4F.View Large Image | View Hi-Res Image | Download PowerPoint SlideThe notion that nuclear proteins travel with mRNAs to the cytoplasm to regulate mRNA function provides an explanation for a series of observations that the nuclear history of an mRNA can affect its cytoplasmic fate. For example, some genes have been shown to require introns for efficient translation of their spliced mRNA products in the cytoplasm (Matsumoto et al. 1998xMatsumoto, K, Wassarman, K, and Wolffe, A.P. EMBO J. 1998; 17: 2107–2121Crossref | PubMed | Scopus (151)See all ReferencesMatsumoto et al. 1998). In addition, as mentioned earlier, introns are necessary to engage the mammalian NMD RNA surveillance pathway that detects nonsense codons by a mechanism with features of the cytoplasmic translational machinery. To explain these observations, it has been hypothesized that RNA binding proteins exist that regulate intron-dependent events in the nucleus and then go on to the cytoplasm to regulate subsequent events. Future studies will be required to test this theory and, if it is true, to identify the specific RNA binding shuttling proteins involved and how they communicate with each other.How RNA binding shuttling proteins themselves are regulated also remains to be determined. Is their distribution between the nucleus and the cytoplasm modulated by environmental cues? Do posttranslational events, such as phosphorylation and methylation, alter their ability to control gene expression events in the nucleus or the cytoplasm? The answer appears to be yes, as a recent study showed that the p38 stress-activated mitogen-activated kinase alters the nucleocytoplasmic distribution of hnRNP A1 in response to osmotic stress, leading to changes of alternative splicing (van der Houven van Oordt et al. 2000xvan der Houven van Oordt, W, Diaz-Meco, M.T, Lozano, J, Krainer, A.R, Moscat, J, and Caceres, J.F. J. Cell Biol. 2000; 149: 307–316Crossref | PubMed | Scopus (224)See all Referencesvan der Houven van Oordt et al. 2000). As stress-activated signaling pathways are fundamental to the life and death of cells, they could play a key role in modulating the functional linkage between mRNA metabolism in the cytoplasmic and nuclear compartments under both physiological conditions and stress responses. The answers to these questions will ultimately tell us much about how communication between the nuclear and cytoplasmic compartments is orchestrated.‡To whom correspondence should be addressed (e-mail: ann-bin.shyu@uth.tmc.edu).