How is mrna exported from nucleus

To eliminate the functionally defective mRNP and ensure translational fidelity, cells have evolved multi-layered surveillance mechanisms. The translation-dependent quality control, which takes place in the cytoplasm, is the best-studied mechanism to degrade defective mRNAs and proteins deposited in mRNP in the nucleus play important roles see [ ] for a recent review. In addition, various nuclear surveillance mechanisms, which closely link to the mRNA export step, are in operation in the nucleus see [ 36 , ] for reviews.

Immature mRNPs containing unspliced transcripts are retained in the nucleus by components of the spliceosome [ , ] and factors associated with the NPCs [ , , ]. The yeast TREX-2 complex has also been shown to contribute to the retention of immature mRNP at the transcription site and nuclear periphery [ ].

In addition, a yeast endoribonuclease Swt1, which transiently associates with the NPC, has been shown to participate in the degradation of defective mRNPs trapped at the nuclear periphery to avoid their cytoplasmic export and translation [ ]. Extensive studies have greatly clarified the molecular mechanisms of mRNA export.

Nuclear mRNA export is fully integrated into gene expression, and it proceeds with other elementary steps of gene expression. The TREX complex plays pivotal roles in the coupling of these processes through the extensive interaction networks with the factors involved in transcription, splicing, polyadenylation, and nuclear export.

The inclusion of a diverse set of adaptor proteins within a single mRNP may increase its chance of being recognized by the transport receptor. Recruitment of multiple copies of transport receptors may also be advantageous for efficient transport of huge mRNPs, as has been suggested for ribosomal particles [ , ]. Alternatively, these adaptor proteins may enable the nuclear export of different mRNPs by a single transport receptor.

As recently suggested, it is also possible that different adaptors function sequentially during the course of mRNP maturation [ 46 ]. However, due to technical difficulties, the protein compositions of individual mRNPs, as well as those of their intermediates still remain to be elucidated.

Detailed analysis of the transcript-specific association of mRNA export factors, especially in mammalian cells, will certainly help answer these open questions. While nuclear mRNA export is essential for eukaryotic cells, it is also crucial for certain pathogens, such as viruses that replicate in the host cell nucleus. As various studies have exemplified, the transport receptor Tap-p15 and the TREX components are exploited to transport viral mRNAs for recent reviews see [ , ].

Although the details remain enigmatic, the mRNA export pathway may include various subroutes that are differentially dependent on particular adaptor proteins. Therefore, a more detailed dissection of the nuclear mRNA export pathway in mammalian cells will be beneficial not only to better understand the general gene expression mechanism, but also to provide information for more practical research applications, such as the development of anti-viral drugs.

I greatly appreciate the anonymous reviewers for their kind help and many constructive comments in improving the manuscript. National Center for Biotechnology Information , U. Journal List Genes Basel v. Genes Basel. Published online Mar Jun Katahira 1, 2.

Rozanne M. Sandri-Goldin, Academic Editor. Author information Article notes Copyright and License information Disclaimer. Received Jan 30; Accepted Mar This article has been cited by other articles in PMC. Introduction Eukaryotic cells consist of various organelles that execute different activities to sustain a range of cellular functions.

Open in a separate window. Figure 1. Figure 2. Figure 3. Splicing-Coupled mRNP formation It has been known for years that splicing stimulates gene expression, but the step at which splicing acts has been elusive see reviews [ 81 , , ] for a discussion of this topic. Figure 4.

Conclusions and Perspectives Extensive studies have greatly clarified the molecular mechanisms of mRNA export. Acknowledgment I greatly appreciate the anonymous reviewers for their kind help and many constructive comments in improving the manuscript. Conflicts of Interest The authors declare no conflict of interest. References 1. Mattaj I. Nucleocytoplasmic transport: The soluble phase. Castello A. Baltz A. The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.

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Biological significance of the importin-beta family-dependent nucleocytoplasmic transport pathways. Gorlich D. Transport between the cell nucleus and the cytoplasm. Cell Dev. Nuclear export of mRNA. Trends Biochem. Segref A. EMBO J. Tan W. Herold A.

Wilkie G. Katahira J. Yang J. Two closely related human nuclear export factors utilize entirely distinct export pathways. Jun L. NXF5, a novel member of the nuclear RNA export factor family, is lost in a male patient with a syndromic form of mental retardation. Sasaki M. Molecular cloning and functional characterization of mouse Nxf family gene products. Nucleic Acids Res. Tretyakova I. Nuclear export factor family protein participates in cytoplasmic mRNA trafficking. Identification and characterization of the mouse nuclear export factor Nxf family members.

Zhou J. Nxf3 is expressed in Sertoli cells, but is dispensable for spermatogenesis. Santos-Rosa H. The Mex67p-mediated nuclear mRNA export pathway is conserved from yeast to human. Reed R. Rodriguez-Navarro S. Linking gene regulation to mRNA production and export. Chanarat S. Tutucci E. Keeping mRNPs in check during assembly and nuclear export. Strasser K. Rodrigues J. Hurt E. Iglesias N.

Genes Dev. Gilbert W. Batisse J. Purification of nuclear poly A -binding protein Nab2 reveals association with the yeast transcriptome and a messenger ribonucleoprotein core structure. Hackmann A. Huang Y. Chang C.

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First, although we speak of a given RNA species as being retained in the nucleus or exported to the cytoplasm, few RNAs are completely nuclear or cytoplasmic at steady state. Instead, each RNA species exists at some point along a spectrum between these two extremes. Few studies have taken all these various factors into account with some exceptions.

Having said that, it is clear that nuclear retention and cytoplasmic export play critical roles in dictating the ultimate distribution of any RNA species. Third, although it is generally true that most mRNAs are well exported, many are not Djebali et al.

Likewise, although there is a general consensus that many lncRNAs are nuclear, it is also clear that several are cytoplasmic, with some studies suggesting that the number of cytoplasmic lncRNAs may be higher than previously thought Wilk et al. Before addressing the question of what sequence determinants impact nuclear export, it becomes necessary to determine whether an RNA which lacks any distinguishing feature is a substrate for nuclear export. In other words, what is the default pathway — nuclear retention or cytoplasmic export?

Three pieces of evidence point to the fact that long RNAs do not require any specialized cis -element for them to be exported from the nuclei of mammalian tissue culture cells. For example, it had been observed that certain reporter mRNAs transcribed from cDNAs were not exported, suggesting that in the absence of splicing, mRNAs are nuclear retained Valencia et al. This confusion was largely due to the fact that it was unclear whether any particular reporter is truly devoid of cis -elements or other distinguishing features that may promote or inhibit mRNA nuclear export.

Importantly, when the newly identified nuclear retention elements were removed, RNAs generated from these reporters were well exported despite the fact that they are not spliced.

In DNA, CG dinucleotides are often methylated, and when these N 5 -methylcytosines undergo spontaneous deamination they are converted to thymidine causing CG dinucleotides to be mutated away in vertebrates Lindahl, In contrast, unmethylated cytosines deaminate to uracils, which are efficiently removed by uracil-DNA glycosylase and reconverted back to cytosines.

Recently it was found that RNAs with significant numbers of CG dinucleotide are substrates for decay, which would effectively prevent their accumulation in the cytoplasm Takata et al. This process likely evolved to protect cells against viral infection.

In the study by Dias et al. It is also possible that these transcripts were spliced and that the researchers were detecting the distribution of lariat introns in their experiments. Additionally, it is conceivable that these RNAs may have other nuclear retention elements.

The last piece of evidence which suggests that nuclear export is the default pathway is that when nuclear localized lncRNAs were analyzed, it was observed that they contained nuclear retention elements Miyagawa et al.

When these nuclear retention elements were removed or mutated, the altered lncRNAs were exported. This allowed researchers to identify two regions that retain this lncRNA in the nucleus by targeting it to nuclear speckles. Moreover, fusion of either of these two nuclear retention fragments to reporters promotes their nuclear retention Lubelsky and Ulitsky, ; Shukla et al.

Taking in all of these lines of evidence, it is likely that in the absence of any active cis -element, a stable RNA that is capped and polyadenylated is a substrate for nuclear export. In eukaryotes, most functional RNAs are extensively processed. Although very strong processing signals are found in regions of the genome that are used to produce functional RNA transcripts be they mRNAs or lncRNAs , weaker processing signals are found throughout the genome.

Thus, robust processing is typically a good indication that the RNA transcript in question is functional and likely encoding a protein Palazzo and Akef, ; Palazzo and Lee, Moreover, many RNA processing machineries directly interact with, and promote the recruitment of, RNA nuclear export factors.

Splicing involves the removal of introns by the spliceosome, which in turn can deposit factors onto the newly spliced RNA. By comparing the localization of these spliced RNAs to transcripts synthesized from cDNAs which lack introns , it has been observed that splicing in some scenarios enhances the extent and the rate of nuclear export Luo and Reed, ; Palazzo et al.

This phenomenon is, however, not universal. Likely, where splicing matters most is in transcripts that happen to have nuclear retention elements. In some cases, splicing can override their activity Akef et al.

The second scenario is probably true for lncRNAs that are efficiently spliced and yet still retained in the nucleus Hacisuleyman et al. Whether it is absolutely required is a bit unclear. The incorporation of non-canonical caps trimethyl-guanosine [3mGpppG], adenosine [ApppG] does not block the export of certain microinjected intronless RNAs, but does block the export of intron-containing mRNAs Palazzo et al.

As detailed below, RNA motifs that are associated with introns are potent nuclear retention signals. Members of this complex interact with Aly Johnson et al. It is, however, likely that these RNAs are never released from RNA polymerase due to the lack of cleavage, complicating the interpretation of this observation. Another observation that suggests that the poly A -tail is not absolutely required for export is that circular RNAs, which lack a tail, are efficiently exported in a UAPdependent manner Huang et al.

Finally, histone mRNAs, which do not have a poly A -tail, are exported by Nxf1 and do not appear to have any export-promoting cis -elements Erkmann et al. Again, as most RNAs exist on a spectrum between being fully nuclear and being fully cytoplasmic, RNA processing events may help to move the RNA closer to the cytoplasmic end of this continuum.

It has been known for quite some time that RNA is extensively modified; however, until recently the majority of these studies focused on these modifications within tRNA and rRNA.

Furthermore, some of these modifications appear to impact nuclear export. Adenosine to inosine editing was the first RNA modification known to affect nuclear export. This reaction occurs specifically in the nucleus and promotes the nuclear retention of these RNAs Zhang and Carmichael, In certain cases nuclear retention of inosine-containing mRNAs can also be used to regulate gene expression Prasanth et al.

Interestingly, this nuclear retention pathway appears to be less active in human embryonic stem cells due to the fact that they do not express the lncRNA NEAT1 , which is required for paraspeckle formation Chen and Carmichael, This includes N 6 -methyladenosine Dominissini et al. Recently, it has been reported that N 6 -methyladenosine promotes the nuclear export of mRNAs Roundtree et al.

Similarly, N 5 -methylcytosine has also been reported to promote mRNA nuclear export by recruiting Aly to the transcript Yang et al. Not only are they modified, but they also tend to contain the start codon in most human genes the start codon is found in internal exons , and are enriched in certain GC-rich motifs that are associated with exon junction complexes Singh et al.

Typically, exon junction complexes are deposited upstream of all newly formed exon-exon splice sites; however, in a subset of genes the exon junction complex also associates with these GC-rich motifs. Importantly, this complex has also been found to bind to nuclear export factors Le Hir et al.

In conclusion, RNA modifications that have been reported to promote export may enhance this process, especially if an RNA has nuclear retention elements; however, it is likely that RNA modifications are not absolutely required to promote export.

These are typically removed by the act of splicing. In its normal life cycle, HIV produces both spliced and unspliced RNAs from the same primary transcript, the latter being used to make late-stage proteins and to generate the RNA-based genome that will be incorporated into new viruses that are assembled in the cytoplasm of the host cell.

Importantly, these unspliced RNAs are retained in the nucleus in early stages by the presence of intronic sequences Chang and Sharp, ; Lu et al. These retention signals can be overcome in late stages by the virally encoded Rev protein, which recognizes the Rev response element, an RNA structure that is present in the late stage RNAs and the viral RNA genome Chang and Sharp, ; Emerman et al.

U1 snRNP recognizes the motif and may recruit nuclear surveillance machinery e. Indeed, when the sequence of the U1 snRNA is altered so that it now base pairs to some other mRNA, these newly targeted transcripts becomes silenced Fortes et al.

A protein component of the U1 snRNP, UK, is required for this inhibition by directly interacting and inhibiting poly A -polymerase Gunderson et al. Interestingly, the nuclear retained RNAs accumulate in nuclear speckles, subnuclear regions where post-transcriptional splicing is thought to occur Dias et al.

Then, the subsequent failure to complete the splicing reaction prevents these RNAs from exiting the nuclear speckles. In agreement with these results, the artificial tethering of UK to a reporter RNA prevents its nuclear export, although the authors did not test for nuclear speckle targeting Takemura et al. This may explain why many poorly exported mRNAs are also localized to nuclear speckles Bahar Halpern et al.

Almada et al. Under normal circumstances these cryptic unstable RNAs are cleaved and degraded. Furthermore, Mtr4 is also a co-activator of the nuclear exosome Schilders et al. It is currently unclear how the PAXT complex would recognize its substrates, although one possibility is that it interacts with U1 that is bound to misprocessed mRNAs. Finally, it should be pointed out that the nuclear retention of mRNAs harboring retained introns may also be used to regulate gene expression.

These retained mRNAs are stable and not subject to degradation. However, in response to some signal, these introns are post-transcriptionally spliced, releasing the mRNAs from the nucleus and triggering protein production. Finally, it also appears that the presence of an intact branch-point sequence in the mature mRNA also promotes nuclear retention in budding yeast Legrain and Rosbash, ; Rain and Legrain, Thus, it is likely that several different intron-associated elements may help to promote the nuclear retention and decay of RNA.

The majority of the human genome is composed of dead transposable elements, constituting half to two-thirds of all DNA Gregory, ; de Koning et al.

When they are present, they usually inhibit nuclear export and promote RNA decay. As described above, if a pair of transposable elements are found in the sense and anti-sense orientation in a single transcript, they can hybridize to form double stranded RNAs. These regions either become substrates for the ADAR enzyme and thus acquire inosine modifications Chen et al.

Typically, PKR is activated by double stranded viruses, however, it is also known to regulate the processing of certain host mRNAs Ilan et al. It remains unclear if PKR activity impacts nuclear export.

It is likely that other features associated with transposable elements are recognized by nuclear retention machinery. A similar C-rich motif that contributed to nuclear retention was found in a large analysis of human lncRNAs Shukla et al.

Since Alu elements are not found outside of primates, lncRNAs must use other elements, especially in non-primates. In addition, it appears that many transposable elements are recognized by particular C2H2 zinc finger proteins Emerson and Thomas, ; Rowe and Trono, ; Schmitges et al.

It has been speculated that when a new transposable element invades a genome, it catalyzes the evolution of novel zinc finger proteins that protects the host. These zinc finger proteins likely repress transposable element activity primarily through transcriptional silencing, although it is also possible that these proteins may help target RNAs for decay or nuclear retention. A few other cis -elements that promote nuclear retention have been characterized in the literature.

As mentioned above, the Rev responsive element promotes nuclear retention Brighty and Rosenberg, ; Nasioulas et al. Palazzo, unpublished observations. In many cases, recruitment of certain proteins to the RNA has been linked to nuclear retention, however, it remains unclear whether the simple presence of their RNA-binding motifs promotes retention more broadly throughout the transcriptome.

Interestingly, both studies found a reasonable number of mRNAs that were poorly exported. Although the distribution of mRNAs with either the nuclear or cytosolic compartment correlated with the association of certain RNA binding proteins, no obvious patterns were discovered. This is in contrast to lncRNAs where the presence of motifs that are either associated with transposable elements Lubelsky and Ulitsky, ; Shukla et al.

One difference may be that nuclear lncRNAs are actively retained while nuclear mRNAs are simply exported to the cytoplasm at a very low rate. This would allow these particular mRNAs to accumulate in the nucleus at high levels. It has been hypothesized that since these large pools of nuclear mRNAs would slowly exit the nucleus, they would supply the cytoplasm with a steady level of mRNA over long periods of time and this could help to buffer the protein translation machinery in the cytoplasm from any wide fluctuations in mRNA production in the nucleus Bahar Halpern et al.

This may be especially important for genes that experience transcriptional bursts, the sporadic production of many mRNAs in a short interval, followed by periods of inactivity Larson, Without this buffering, mRNA levels in the cytoplasm would stochastically increase and decrease over short intervals of time, especially if the mRNA has a short half-life.

A few studies have uncovered large RNA elements that have nuclear retention activity but remain ill-defined. This nuclear retention activity can be overcome by either extending the length of the transcript Akef et al. Deleting the first or the second half of this nucleotide region does not disrupt nuclear retention, suggesting that there may be multiple sequences that account for this activity. Despite this, the two halves do not share any obvious motif or structure.

In the case of region E which is about 1KB in length, elimination of the first or last half disrupts its activity. For region M, its activity maps to nucleotides, but it is disrupted if it is truncated any further. Ultimately, it remains possible that these pieces of RNA contain one or more discrete motifs or structures that have weak nuclear retention activity Shukla et al.

Many viral elements are known to promote nuclear export; however, a number of these act to overcome nuclear retention elements such as the presence of unspliced introns. Besides the Rev responsive element described above , the most well studied is the constitutive transport element CTE of type D retroviruses Bray et al.

Some mRNAs have been described to have cis -elements that promote nuclear export. Instead they use the CRM1 nuclear transport receptor, which promotes the export of proteins. Finally, it has been reported that naturally intronless transcripts contain specialized cytoplasmic accumulation region elements CAR-E , which recruit specific complexes to the RNA Lei et al. Some of the interpretations of these experiments are complicated by the fact that CAR-Es were fused to reporters harboring nuclear retention elements whose activity can be overcome by simply extending the length of the transcript see Discussion in Akef et al.

Thus, the functional relevance of these purported export-promoting elements seems unclear at this time. It is likely that bone fide export-promoting elements, such as the CTE, function by overcoming the activity of nuclear retention elements, such as the ones present in mRNAs with retained introns. In particular, the nuclear retention and degradation of spurious transcripts eliminates much of the harm caused by junk RNA and hence reduces the deleteriousness of cryptic TSSs and intergenic DNA regions that harbor such sites Palazzo and Akef, ; Palazzo and Gregory, ; Palazzo and Lee, It is likely that these non-functional transcripts act as the raw substrates for natural selection and some are converted into novel functional lncRNAs.

The idea that neutral mutations i. Likely, this is a step by step process where new entities are created by non-adaptive processes and then acquire functions which can be selected for by natural selection. One example is presented in Figure 4. First, random mutations create and destroy cryptic TSSs.

If the resulting altered histone modifications impart some benefit by regulating nearby genes in a way that improves the fitness of the organism, then the transcriptional event and its cryptic TSS will be selectively retained. Eventually the ncRNA generated from these loci, which is initially a by-product, may act as a platform to help assemble chromatin remodeling complexes in the vicinity of their target genes.

This conversion process may frequently occur in tissues that have a high amount of spurious transcription, such as in developing spermatids Kaessmann, ; Jandura and Krause, During sperm development, DNA is unpackaged from histones and then repackaged into protamines. This transiently exposed DNA can act as a non-specific substrate for RNA polymerases causing high levels of spurious transcription. Once a ncRNAs acquires some associated function in the testes, it can subsequently be expressed in other tissues.

In particular, by retaining and degrading misprocessed mRNAs, they are not efficiently translated into proteins and do not cause much harm to the organism. This reduces the deleteriousness of splicing and polyadenylation errors and prevents their elimination by natural selection. This may explain why splicing appears to be inherently sloppy in mammalian cells. In support of this idea, it has been widely noted that although most genes are alternatively spliced, they typically give rise to only one polypeptide Tress et al.

These elements then act as the raw substrates necessary for the evolution of functional alternative splicing events. This is another example of constructive neutral evolution in action. Over the past few years, we have gained a fuller picture of the rules that dictate RNA distribution to these two compartments.

We have established that any stable long RNA is a substrate for nuclear export unless it contains a nuclear retention element. Undoubtably, splicing and other RNA processing events further enhance nuclear export.

In addition, RNA modifications also play an important role in this process. Although our understanding of the major components that drive export are well known, we still must identify nuclear retention complexes and determine their mode of action to obtain a full picture of how the nuclear and cytoplasmic transcriptomes are achieved. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Cell 83 , — Bayliss, R. Cell , 99— Download references. We would like to acknowledge critical reading of the manuscript by the members of the Hurt laboratory and by S. You can also search for this author in PubMed Google Scholar. Correspondence to Ed Hurt. The signal recognition particle is an evolutionarily conserved RNA—protein complex that contains a 7S RNA species and targets integral membrane and secretory proteins to the translocation machinery of the endoplasmic reticulum. Processing bodies.

A large multiprotein complex that brings together the Sm proteins and small nuclear RNAs, thereby facilitating small nuclear ribonucleoprotein assembly. A set of seven proteins that are arranged as a ring structure on a specific small nuclear RNA-binding site to become part of spliceosomal small nuclear ribonucleoproteins. An abundant class of proteins that are involved in various aspects of mRNA metabolism. A process by which a cell destroys mRNAs for which translation has been prematurely terminated owing to the presence of a nonsense codon in the coding region.

InsP 6. One of many small messenger phosphoinositides that is found in cells. InsP 6 is synthesized by IPK1 from inositol 1,4,5-trisphosphate InsP 3 , a precursor that also regulates the release of intracellular calcium. Reprints and Permissions. Exporting RNA from the nucleus to the cytoplasm.