id: PW:0001587 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0001587 title: mrna nuclear export pathway description: 'Mature mRNA - the pre-mRNA that has been 5''capped, spliced and 3'' polyadenylated, has to reach the cytoplasm in order to serve as the template for protein translation. Its directional transport through the nuclear pore complex (NPC) is a critical aspect of regulated gene expression. While the above steps/pathways have many times been described separately, it is now known that they are intimately intertwined. Transport is linked to transcription and to the processing events with which transcription is associated. NPCs are massive macromolecular complexes embedded in the nuclear envelope (NE), or membrane - the structure that separates the nuclear and cytoplasmic compartments of eukaryotic cells. The NE is composed of an inner and outer nuclear membrane - INM and ONM, respectively, separated by a luminal space. The INM and ONM, the latter contiguous with the endoplasmic reticulum (ER), are fused at sites of NPC insertion. The INM contains transmembrane proteins that interact with the nuclear lamina and chromatin underneath the NE. Some INM proteins also interact with ONM resident proteins to link the cytoskeleton with the nuclear lamina. NPC structure exhibits an eight-fold rotational symmetry, it contains a membrane-embedded scaffold encompassing the central transport channel, and a cytoplasmic and nuclear ring, each with eight filaments attached. The nuclear filaments are further connected to a distal nuclear ring, forming the ''nuclear basket''. These elements consist of multiple copies of ~30 nucleoporins (NUPs) with different, and relatively short, resident lifetimes, except for the scaffold proteins. Of the few domains of NUPs, the phenylalanine-glycine (FG) repeats are the most common; FG-NUPs with 4 to 48 FG repeats line the central channel forming a meshwork that controls traffic. Others, FG and non-FG, are present within other structural compartments of the NPC. Some form distinct sub-complexes, of which the so-called Y-complex (because of its shape), represents a building block of the NPC scaffold. Its importance for mRNA export is conserved across species (also known as Nup84 in yeast and Nup107 in humans). In addition to mRNA export, it also fulfills other functions. The NPC, in addition to mediating traffic between the two cellular compartments, is involved in the regulation of genome architecture and gene expression, exhibits tissue specific expression and plays a role in development and differentiation. The overall topology of the NPC is conserved from yeast to humans. In metazoans, two major transport receptors are recruited to NPCs to mediate two distinct export pathways: the CRM1 and the NXF1-NXT1 heterodimer, of which the latter is the major yeast system (Mex67-Mtr2); NXF1-NXT1 is also known as Tap-p15. The bulk of mRNA is exported via the NXF1-NXT1 system while a smaller subset of mRNA and other RNA particles are exported via CRM1. Either receptor relies on adaptor proteins to couple to cargo. Various proteins associate/dissociate with mRNA during its export stages, effectively accounting for a dynamic m-ribonucleoprotein (mRNP) entering the ''nuclear basket'', traversing the channel and exiting at the cytoplasmic filaments of NPCs. Selective interactions of receptors and NUPs facilitate translocation through the NPC. Conformational and compositional changes of mRNP occur as it exits the channel and enters the cytoplasm, referred to as ''remodeling'' and they are thought to assure directionality of export by promoting the recycling of transporters and adaptors into the nucleus. Defects or aberrant expression of components of mRNA nuclear export have been associated with human diseases and many cancer types. Molecular details of the individual routes are described below. NXF1-NXT1 export pathway NXF1-NXT1 export is the main mRNA transport pathway. In the NXF1-NXT1 system, the TREX complex, also known as TREX/THO, plays an essential role. TREX is co-transcriptionally recruited and couples export with elongation in yeast and with splicing in metazoans. The TREX/THO complex consists of TREX elements Aly/Ref, DDX39B, known as UAP56 and Sarnp, known as Cip29 and a multi-subunit THO; Aly/Ref acts as an adaptor for Nfx1. Thoc5 along with Aly/REF induce a conformational change in Nxf1 that exposes its RNA-binding domain. Nxf1 acts as a heterodimer in partnership with Nxt1. At the cytoplasmic face, the mRNA export factor Gle1 and its cofactor inositol hexakisphosphate or phytate/phytic acid (IP6), and associated DEAD-box protein Ddx19, are involved in remodeling/cargo release. Ddx19 is specifically bound to Nup214 and its RNA-dependent ATPase activity relies on Gle1-IP6 stimulation and Nup214-triggered ADP release. Several FG-NUPs and non-FG-NUPs are required for transport through NPC via specific interactions they establish with the transport receptors. Most studies have been carried out in yeast; however, the vertebrate orthologs are likely to be important for this route of mRNA nuclear export, as experiments carried out in these systems have begun to unveil. CRM1 export pathway CRM1 - exportin 1 (XPO1), mediates several flavors of RNA export, depending on the adaptors that recruit it to cargo, some to particular cis-mRNA elements. All harbor the nuclear export sequence (NES) that facilitates the interaction with the receptor. These include leucine-rich pentatricopeptide repeat domain (LRPPRC), the RNA-binding protein human antigen R (HuR/ELAVL1) and the nuclear export factor 3 (NFX3). Lrpprc recruits Xpo1 and EIF4E to eIF4E-sensitivity element (4E-SE)-containing mRNA, Elavl1 (HuR) recruits Anp32a, known as pp32 and Anp32b, known as APRIL, to AU-rich element (ARE)-containing mRNA to facilitate its interaction with Xpo1 and finally, a third flavor of CRM1-mediated export is via Nxf3 recruitment of Xpo1. Xpo1 is a member of the importin beta superfamily of nucleocytoplasmic receptors; importins and exportins, known as karyopherins, need the presence of GTP-bound Ran GTPase to bind cargo and, as the names suggest, are involved in bi-directional transport through the NPC. Ran is a member of the Ras superfamily of small monomeric G proteins. The CRM1-mediated export routes share in common the cargo release, dependent upon RanGTP hydrolysis, which is coordinated by Ranbp1 and Ranbp2, and RanGAP. Of note is that in addition to exporting a subset of RNAs, the CRM1 system can export viral RNA and is a major protein export system. Several FG-NUPs and non-FG-NUPs are required for transport through NPC via specific interactions they establish with the transport receptors; Nup98 for instance, is known to be important for the CRM1-mediated routes.' diagram_image: https://rgd.mcw.edu/pathway/PW0001587/mRNA%20nuclear%20export%20pathway/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0001587/mRNA%20nuclear%20export%20pathway/mRNA%20nuclear%20export%20pathway.gpp diagram_pathway_links: - id: PW:0001073 label: spliceosome pathway - id: PW:0001578 label: 5'-end pre-mRNA capping pathway - id: PW:0001579 label: 3'-end pre-mRNA processing pathway - id: PW:0001625 label: NXF1-NXT1 export pathway - id: PW:0001626 label: CRM1 export pathway diagram_gene_links: - id: RGD:2116 label: Anp32a - id: RGD:621285 label: Anp32b - id: RGD:1593382 label: Ddx19b - id: RGD:69647 label: Eif4e - id: RGD:1308649 label: Elavl1 - id: RGD:1307329 label: Gle1 - id: RGD:1306575 label: Lrpprc - id: RGD:62014 label: Nxf1 - id: RGD:1564923 label: Nxf3 - id: RGD:1309327 label: Nxt1 - id: RGD:620367 label: Ran - id: RGD:1310521 label: Ranbp1 - id: RGD:1560047 label: Ranbp2 - id: RGD:1310380 label: Rangap1 - id: RGD:620517 label: Xpo1 diagram_chemicals: - id: CHEBI:15996 label: GTP diagram_edges: - source: 3'-end pre-mRNA processing pathway relation: positively_affects target: mature mRNA - source: 4E-SE mRNA relation: associated_with target: Lrpprc - source: 4E-SE mRNA relation: positively_affects target: cargo release - source: 5'-end pre-mRNA capping pathway relation: positively_affects target: mature mRNA - source: ARE mRNA relation: associated_with target: Elavl1 - source: ARE mRNA relation: positively_affects target: cargo release - source: Anp32a relation: associated_with target: ARE mRNA - source: Anp32a relation: associated_with target: Elavl1 - source: Anp32a relation: associated_with target: Xpo1 - source: Anp32b relation: associated_with target: ARE mRNA - source: Anp32b relation: associated_with target: Elavl1 - source: Anp32b relation: associated_with target: Xpo1 - source: Eif4e relation: associated_with target: Lrpprc - source: Lrpprc relation: associated_with target: Xpo1 - source: Nxf1 relation: associated_with target: Nxt1 - source: Nxf1 relation: associated_with target: TREX/THO complex - source: Nxf3 relation: associated_with target: Xpo1 - source: Ran relation: associated_with target: Xpo1 - source: Ranbp1 relation: positively_affects target: Ran. - source: Ranbp2 relation: positively_affects target: Ran. - source: Rangap1 relation: positively_affects target: Ran. - source: mature mRNA relation: associated_with target: Nxf3 - source: mature mRNA relation: associated_with target: TREX/THO complex - source: mature mRNA relation: positively_affects target: cargo release - source: spliceosome pathway relation: positively_affects target: mature mRNA diagram_labels: - 4E-SE mRNA - ARE mRNA - cargo release - GDP - Gle1 --+> Ddx19b - mature mRNA - mRNA maturation pathway diagram_other_links: - href: /wg/home/pathway2/molecular-pathways2/nuclear-pore-complex2 label: Nuclear Pore Complex - href: /wg/home/pathway2/molecular-pathways2/trex/tho-complex label: TREX/THO complex - href: http://en.wikipedia.org/wiki/Phytic_acid label: phytate references: - id: RGD:9743947 citation: 'Bonnet A and Palancade B, Genes (Basel). 2014 Sep 2;5(3):767-91. doi: 10.3390/genes5030767.' - id: RGD:9743960 citation: 'Katahira J Biochim Biophys Acta. 2012 Jun;1819(6):507-13. doi: 10.1016/j.bbagrm.2011.12.001. 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