id: MODULE:mrna_nuclear_export title: Human mRNA nuclear export — TREX loading on spliced mRNA, NXF1-NXT1 handover, nuclear pore translocation and DDX19-GLE1 remodelling, with the CRM1 route for specific mRNAs; THOC1/THOC2/THOC3/THOC5/THOC6/THOC7/DDX39B/ALYREF/CHTOP/SARNP/NXF1/NXT1/MCM3AP/ENY2/PCID2/DDX19B/GLE1/NUP214/XPO1/RAN description: >- A mature mRNA, capped, spliced and polyadenylated in the nucleus, must cross the nuclear pore complex (NPC) before it can be translated. In human cells bulk export is coupled to splicing and to the cap. The transcription-export complex TREX, built from the multi-subunit THO complex (THOC1, THOC2, THOC3, THOC5, THOC6, THOC7) with the DEAD-box ATPase UAP56 (DDX39B) and the export adaptors ALYREF, CHTOP and CIP29 (SARNP), is deposited near the 5' end of the spliced mRNA through an interaction between ALYREF and the cap-binding protein CBP80. UAP56 uses its ATPase cycle to load ALYREF and CHTOP onto the mRNA. The adaptors then recruit the export receptor, the NXF1-NXT1 (TAP-p15) heterodimer: ALYREF and THOC5 contact NXF1 and switch it from an autoinhibited state into one that exposes its arginine-rich RNA-binding domain, and the mRNA is handed over from ALYREF to NXF1. TREX-2 (GANP/MCM3AP with ENY2 and PCID2), anchored on the nuclear basket, helps deliver NXF1-bound mRNPs to the pore. NXF1-NXT1 carries the mRNP through the central channel by transient contacts between its NTF2-like and UBA domains and the phenylalanine-glycine (FG) repeats of the nucleoporins, on a scaffold whose outer rings are built from the Nup107-160 (Y) complex. At the cytoplasmic filaments the DEAD-box ATPase DDX19 (DDX19B), anchored on NUP214, is activated by GLE1 and its small-molecule cofactor inositol hexakisphosphate (IP6). DDX19 remodels the emerging mRNP, stripping export factors so that they recycle to the nucleus and making the passage directional. A minority of mRNAs leave by a second, Ran-dependent route through the karyopherin CRM1 (XPO1), which is recruited by mRNA-specific adaptors: LRPPRC with eIF4E for mRNAs that carry the eIF4E-sensitivity element, HuR (ELAVL1) with pp32 and APRIL (ANP32A, ANP32B) for AU-rich-element mRNAs, NXF3, and FMRP for N6-methyladenosine-marked mRNAs. RanGTP loads the cargo onto CRM1 in the nucleus, and GTP hydrolysis by Ran, stimulated by RanGAP1 with RanBP1 and RanBP2 at the cytoplasmic face, releases it. status: DRAFT scope: CONCRETE evidence: - source_id: PW:0001587 title: mRNA nuclear export pathway statement: >- The module boundary follows the RGD Pathway Ontology term, its record text and its interactive diagram. The diagram draws mature mRNA associated with the TREX/THO complex, Nxf1 associated with Nxt1 and with the TREX/THO complex, Gle1 acting on Ddx19b at the cytoplasmic face, and a CRM1 branch in which Xpo1 is associated with Ran, Lrpprc (with Eif4e and 4E-SE mRNA), Anp32a and Anp32b (with Elavl1 and ARE mRNA) and Nxf3, while Ranbp1, Ranbp2 and Rangap1 positively affect Ran and the routes converge on "cargo release". The record text adds the TREX subunits, the NPC with its FG-nucleoporins and the Nup107 (Y) complex, and IP6 as the Gle1 cofactor. Upstream sub-pathways (spliceosome, capping and 3'-end processing) are drawn as inputs producing mature mRNA. Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0001587.yaml). - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0001587.yaml title: RGD PW:0001587 pathway description statement: RGD's description of the two export routes the module models. supporting_text: "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." - source_id: PW:0001625 title: NXF1-NXT1 export pathway statement: >- The RGD sub-pathway for the bulk route, linked from the PW:0001587 diagram and described in its record text. Every step of it (TREX loading, NXF1-NXT1 handover, NPC translocation and DDX19/GLE1 remodelling) is modelled here as a required part. - source_id: GO:0006406 title: mRNA export from nucleus statement: >- The curated exactMatch recorded for PW:0001587 in the RGD_PATHWAY_ONTOLOGY project, and this module's process concept. Both routes, NXF1-NXT1 and CRM1, export mRNA, so the parent term rather than GO:0016973 poly(A)+ mRNA export from nucleus is used for the module as a whole. - source_id: gomodel:63894f2500001748 title: FRM1 binds N6-methyladenosine (m6A)-containing mRNAs and promotes their nuclear export (Human) statement: >- The only production human GO-CAM in which an mRNA export activity is modelled (checked gocams/index.tsv, November 2026). It has XPO1 enabling GO:0005049 nuclear export signal receptor activity and FMR1 enabling GO:1990247 N6-methyladenosine-containing RNA reader activity, both part of GO:0006406, and grounds this module's CRM1 route. No production GO-CAM models TREX, NXF1-NXT1 or the DDX19-GLE1 step. - source_id: PMID:11979277 title: TREX is a conserved complex coupling transcription with messenger RNA export. statement: >- Defines TREX as the THO complex plus the export factors Aly and UAP56, conserved from yeast to human. supporting_text: Both Aly and UAP56 associate with human counterparts of the THO complex. - source_id: PMID:20005110 title: mRNA export from mammalian cell nuclei is dependent on GANP. statement: >- Summarises the bulk route in mammalian cells: NXF1 binds the mRNP through adaptors and crosses the NPC by transient FG-nucleoporin contacts. supporting_text: Bulk nuclear export of messenger ribonucleoproteins (mRNPs) through nuclear pore complexes (NPCs) is mediated by NXF1. It binds mRNPs through adaptor proteins such as ALY and SR splicing factors and mediates translocation through the central NPC transport channel via transient interactions with FG nucleoporins. notes: >- Derived from the RGD Pathway Ontology term PW:0001587 (mRNA nuclear export pathway) through the RGD_PATHWAY_ONTOLOGY project's diagram->module route. RGD curates 37 human genes to it. All 37 are modelled: the TREX subunits ALYREF, DDX39B, SARNP and THOC1/2/5/6/7; NXF1 and NXT1; the nucleoporins NUP62, NUP54, NUP58, NUP98, NUP153 and NUP214 and the Y-complex members NUP107, NUP133, NUP160, NUP85, NUP37, NUP43, SEC13 and SEH1L; DDX19B and GLE1; and the CRM1 branch XPO1, RAN, RANGAP1, RANBP1, RANBP2, LRPPRC, EIF4E, ELAVL1, ANP32A, ANP32B and NXF3. Added beyond the RGD list, each with its own evidence: THOC3 (the Tex1 subunit, present in the fly module and in TREX by GO's definition), CHTOP, POLDIP3 and ZC3H11A (TREX adaptors shown biochemically to join human TREX), the TREX-2 subunits MCM3AP (GANP), ENY2 and PCID2, and FMR1 (from the human GO-CAM). The mapped GO process GO:0006406 is the module concept. Of the diagram's sub-pathway links, the NXF1-NXT1 export pathway (PW:0001625) is fully modelled and listed as evidence; the CRM1 export pathway is modelled only for its mRNA branch, because CRM1 also exports proteins, snRNA and ribosomal subunits, so that RGD term is mentioned here but not claimed. The spliceosome, 5' capping and 3'-end processing sub-pathways are upstream inputs that produce the mature mRNA and are outside the boundary. Fly counterpart. modules/dmel_mrna_nuclear_export.yaml models the conserved core from the FlyBase TREX, THO-C, TREX-2 and NXF gene groups: TREX (Hel25E, Ref1, THO, tex), the Nxf1-Nxt1 receptor (sbr, Nxt1) and TREX-2 (xmas, PCID2, e(y)2), and puts the NPC and the EJC outside. This module keeps those three parts in the same order and with the same complex terms, so the two can be compared directly, and adds what the RGD pathway adds: the NPC translocation step, the DDX19-GLE1 remodelling step and the CRM1 route. Two small differences: TREX-2 is marked optional here (in human cells it behaves like a basket component and its depletion slows export rather than abolishing it, PMID:23591820), and the NXF1-NXT1 complex is grounded on GO:0042272 nuclear RNA export factor complex, whose exact synonyms are "NXF1-NXT1 complex" and "TAP-p15 complex". The fly module states that GO has no CC term for this heterodimer; GO:0042272 is that term and could be used there. The fly module is referenced in prose only, since a cross-species module_ref would assert an identity this module does not need. Nuclear pore. No human nuclear pore complex module exists in modules/ (only dmel_nuclear_pore_complex), so module_ref was not used and the pore is modelled inline as a required transport step with two complex annotons: the FG-nucleoporins the receptor contacts (NUP62, NUP54, NUP58, NUP98, NUP153) and the Y-complex scaffold. They are parts, not context, because RGD includes them in the pathway and the receptor-FG contact is the translocation mechanism, but the step is a shared transport organelle used by every karyopherin route, and if a human NPC module is written later this step should become a module_ref to it. The Y-complex annoton carries no mRNA-export process: it is the scaffold the FG layer sits on, and its contribution to export is structural. NUP96, which is produced from the same NUP98 precursor and belongs to the Y-complex, shares NUP98's accession and is represented only through it. TPR and NUP50 of the basket, NUP88 and NUP42 (hCG1, the GLE1 anchor) of the cytoplasmic face and the other nucleoporins are not listed; NUP42 is omitted because no cached human evidence for its GLE1 role was available. Boundary decisions. (1) TREX-2 is an optional part rather than context, following the fly module and the GANP evidence that it binds NXF1 and is needed for efficient NXF1 recruitment to pores. Its centrin (CETN2/CETN3) and DSS1 (SEM1) subunits, known from yeast and human biochemistry, are not listed. (2) The exon junction complex is context, not a part, as in the fly module. It is deposited by splicing and some of its components help recruit TREX, but its core function is in mRNA localisation, translation and nonsense-mediated decay, and RGD does not include it. The cap-binding complex (CBP80/NCBP1), which recruits TREX through ALYREF, and the SR-protein export adaptors (SRSF3, SRSF7) that also hand mRNA to NXF1 are likewise context, recorded in prose. (3) The CRM1 route is included as an optional part because it is half of the RGD pathway and is the route of the only production human mRNA export GO-CAM. Its adaptors form a ROUTE variant set, since they define different mRNA classes, not interchangeable carriers of one activity. RAN, RANGAP1, RANBP1 and RANBP2 are modelled inside the CRM1 part as the Ran cycle that drives cargo loading and release; the RanGDP import and RCC1 recharging steps of the Ran cycle are outside. NUP98's role in the CRM1 routes is noted on its unit rather than duplicated. (4) DDX39A (URH49), the paralog of UAP56, can substitute for it in TREX-like complexes, and DDX19A is a paralog of DDX19B; neither is in the RGD list and neither is modelled. The one human GO-CAM containing DDX39A (gomodel:66c7d41500002513) models it as a negative regulator of immune-related RNA export and is not linked here. (5) Inositol hexakisphosphate is named in prose and in GLE1's function (GO:0000822) rather than as a separate participant; its synthesis by IPMK and IPPK is outside the boundary. Molecular functions were taken from each protein's GO annotations in QuickGO (checked November 2026), preferring experimental rows. DDX39B GO:0003724 RNA helicase activity (IDA); ALYREF GO:0003729 mRNA binding (IBA, with direct binding shown in PMID:18364396); THOC2 GO:0003729 (IBA); THOC5 GO:0030674 protein-macromolecule adaptor activity (IBA); NXF1 GO:0003729 (its GOA rows are GO:0003723 RNA binding by HDA/IBA; the mRNA-specific child is used on the strength of PMID:18364396); nucleoporins GO:0017056 structural constituent of nuclear pore (IDA/IMP for NUP107, NUP133, NUP160, NUP153, NUP98; IBA for the rest); DDX19B GO:0003724 (IBA; GO:0016887 ATP hydrolysis activity by EXP); GLE1 GO:0000822 inositol hexakisphosphate binding (IBA); XPO1 GO:0005049 nuclear export signal receptor activity (IDA/IMP); RAN GO:0003924 GTPase activity (IDA); RANGAP1 GO:0005096 GTPase activator activity (IDA); EIF4E GO:0000340 RNA 7-methylguanosine cap binding (IDA); LRPPRC GO:0003729 (IDA; core in its gene review); ELAVL1 GO:0035925 mRNA 3'-UTR AU-rich region binding (IDA; core in its gene review); NXF3 GO:0003723 RNA binding (IBA); FMR1 GO:1990247 (from the GO-CAM). Units with no GO function that describes their role here (CHTOP, SARNP, POLDIP3, ZC3H11A, THOC1/3/6/7, NXT1, MCM3AP, ENY2, PCID2, NUP37, NUP43, SEC13, SEH1L, RANBP1, RANBP2, ANP32A, ANP32B) carry either no function or a free-text preferred_term, rather than an off-role GO term such as CHTOP's methyl-CpG binding or ANP32B's histone binding. Bare protein binding is not used. GO has no molecular-function term for an mRNA export receptor or export adaptor (GO:0140142 nucleocytoplasmic carrier activity is do-not-annotate, and GO:0005049 is defined by the protein NES), which is why NXF1 and ALYREF carry mRNA binding; this is an ontology gap, not a biological one. GO-CAM and GOA observations. gocams/index.tsv (November 2026) has one production human model of mRNA export, gomodel:63894f2500001748 (FMRP-XPO1, m6A mRNAs), linked from the XPO1 and FMR1 annotons, and its mouse counterpart gomodel:63894f2500001789. The seed's best GO-CAM lead is that same model. No production GO-CAM models TREX, NXF1-NXT1, TREX-2, the NPC step or DDX19-GLE1, which is the largest curation gap the module reveals. RAN's only GO-CAM (gomodel:61f34dd300000863) and RANBP2's (gomodel:66c7d41500002513) model protein export and SUMOylation respectively and are not linked. Two possible upstream issues: GLE1 has no annotation to GO:0001671 ATPase activator activity although activation of DDX19 is its defining activity (yeast Gle1 evidence; human data would be needed for a direct annotation), and NUP214 and NUP42 carry GO:0005049 nuclear export signal receptor activity by IDA/IBA, a karyopherin term that does not obviously describe a nucleoporin and is worth an upstream look. Gene reviews exist only for NUP98, LRPPRC and ELAVL1; LRPPRC's review treats its nuclear export role as non-core next to its mitochondrial function, which this module respects by placing it only in an optional route. PANTHER family ids and PTNs are not asserted. module: id: mrna_nuclear_export label: mRNA export from nucleus (human) module_type: BIOLOGICAL_PROCESS concepts: - preferred_term: mRNA export from nucleus term: id: GO:0006406 label: mRNA export from nucleus context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens cellular_components: - preferred_term: nucleus term: id: GO:0005634 label: nucleus description: >- Where TREX assembles on the spliced mRNA and NXF1-NXT1 or CRM1 is loaded. - preferred_term: nuclear envelope term: id: GO:0005635 label: nuclear envelope description: >- Where the nuclear pores the mRNP crosses sit, with the nuclear basket (TREX-2 docking) on one face and the cytoplasmic filaments (DDX19-GLE1 remodelling, Ran GTP hydrolysis) on the other. The nuclear pore itself is a protein complex, not an anatomical entity, so it and its basket and filament subcomplexes are given on the annotons that act there rather than as module context. parts: - order: 1 role: TREX assembly on the spliced, capped mRNA node: id: trex_assembly label: TREX loading on spliced mRNA module_type: BIOLOGICAL_PROCESS description: >- The THO complex associates with spliced but not unspliced mRNA and is recruited near the 5' cap through an ALYREF-CBP80 contact, so recruitment is coupled to splicing and capping rather than directly to transcription. UAP56 (DDX39B) bridges THO to the adaptors in an ATP-dependent way and, with its ATPase activated by ALYREF and CHTOP, loads those adaptors onto the mRNA. The result is an export-competent mRNP that carries the binding sites for NXF1. evidence: - source_id: PMID:15998806 statement: Human THO associates with spliced mRNA, so TREX recruitment is splicing-coupled. supporting_text: Here we report the identification of the human THO complex and show that it associates with spliced mRNA, but not with unspliced pre-mRNA in vitro. - source_id: PMID:17190602 statement: TREX is recruited to the 5' end of the mRNA via an ALYREF-CBP80 interaction. supporting_text: CBP80, which is bound to the cap, associates efficiently with TREX, and Aly mediates this interaction. - source_id: PMID:20844015 statement: TREX assembly is ATP-dependent, with UAP56 bridging THO to ALYREF and CIP29. supporting_text: We show that UAP56 mediates an ATP-dependent interaction between the THO complex and both CIP29 and Aly, indicating that TREX assembly is ATP-dependent. annotons: - id: trex_complex label: TREX complex on spliced mRNA participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: transcription export complex (TREX) term: id: GO:0000346 label: transcription export complex active_units: - id: ddx39b label: UAP56 (DDX39B) role: ATP-dependent loader of the export adaptors onto mRNA participant: selector_type: GENE_PRODUCT gene_product: preferred_term: DDX39B term: id: UniProtKB:Q13838 label: Spliceosome RNA helicase DDX39B function: preferred_term: RNA helicase activity term: id: GO:0003724 label: RNA helicase activity evidence: - source_id: PMID:23299939 statement: >- ALYREF and CHTOP stimulate UAP56's ATPase and helicase activities, and UAP56 recruits both adaptors onto mRNA. DDX39B carries GO:0003724 by IDA in GOA. supporting_text: We show that both Chtop and Alyref activate the ATPase and RNA helicase activities of Uap56 and that Uap56 functions to recruit both Alyref and Chtop onto mRNA. - id: alyref label: ALYREF (Aly/REF, THOC4) role: export adaptor that binds mRNA and the cap-binding complex and hands the mRNA to NXF1 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ALYREF term: id: UniProtKB:Q86V81 label: THO complex subunit 4 function: preferred_term: mRNA binding term: id: GO:0003729 label: mRNA binding evidence: - source_id: PMID:18364396 statement: REF/ALY binds mRNA and transfers it to TAP (NXF1) in a ternary complex. supporting_text: Here, we show that REF/ALY binds mRNA; but upon formation of a ternary complex with TAP the RNA is transferred from REF to TAP, and overexpression of TAP displaces REF from mRNA in vivo. - id: chtop label: CHTOP role: arginine-methylated TREX adaptor that stimulates UAP56 and binds the NTF2-like domain of NXF1 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CHTOP term: id: UniProtKB:Q9Y3Y2 label: Chromatin target of PRMT1 protein function: preferred_term: UAP56 ATPase stimulation and NXF1 recruitment (no GO molecular function asserted) evidence: - source_id: PMID:23299939 statement: CHTOP is a TREX component that binds NXF1 in a methylation-dependent manner. supporting_text: As observed with the THO complex subunit Thoc5, Chtop binds to the NTF2-like domain of Nxf1, and this interaction requires arginine methylation of Chtop. - id: sarnp label: CIP29 (SARNP) role: TREX component recruited via UAP56 in an ATP-dependent manner (Tho1 relative) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SARNP term: id: UniProtKB:P82979 label: SAP domain-containing ribonucleoprotein evidence: - source_id: PMID:20844015 statement: CIP29 is a TREX component with a yeast relative and a role in mRNA export. supporting_text: Here, we carried out proteomic analysis of immunopurified human TREX complex and identified the protein CIP29 as the only new component with a clear yeast relative (known as Tho1). - id: thoc1 label: THOC1 role: THO subunit (Hpr1 homolog) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: THOC1 term: id: UniProtKB:Q96FV9 label: THO complex subunit 1 - id: thoc2 label: THOC2 role: THO scaffold subunit (Tho2 homolog) that contacts RNA participant: selector_type: GENE_PRODUCT gene_product: preferred_term: THOC2 term: id: UniProtKB:Q8NI27 label: THO complex subunit 2 function: preferred_term: mRNA binding term: id: GO:0003729 label: mRNA binding - id: thoc3 label: THOC3 role: THO subunit (Tex1 homolog) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: THOC3 term: id: UniProtKB:Q96J01 label: THO complex subunit 3 - id: thoc5 label: THOC5 role: THO subunit that, with ALYREF, contacts NXF1 and opens its RNA-binding domain participant: selector_type: GENE_PRODUCT gene_product: preferred_term: THOC5 term: id: UniProtKB:Q13769 label: THO complex subunit 5 function: preferred_term: protein-macromolecule adaptor activity term: id: GO:0030674 label: protein-macromolecule adaptor activity - id: thoc6 label: THOC6 role: THO subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: THOC6 term: id: UniProtKB:Q86W42 label: THO complex subunit 6 - id: thoc7 label: THOC7 role: THO subunit participant: selector_type: GENE_PRODUCT gene_product: preferred_term: THOC7 term: id: UniProtKB:Q6I9Y2 label: THO complex subunit 7 - id: poldip3 label: POLDIP3 (PDIP3) role: metazoan-specific TREX component recruited in an ATP-dependent manner participant: selector_type: GENE_PRODUCT gene_product: preferred_term: POLDIP3 term: id: UniProtKB:Q9BY77 label: Polymerase delta-interacting protein 3 evidence: - source_id: PMID:22928037 statement: PDIP3 and ZC11A are components of a common TREX complex and function in mRNA export. supporting_text: Our data indicate that both of these proteins are components of a common TREX complex and function in mRNA export. - id: zc3h11a label: ZC3H11A (ZC11A) role: metazoan-specific TREX component recruited in an ATP-dependent manner participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ZC3H11A term: id: UniProtKB:O75152 label: Zinc finger CCCH domain-containing protein 11A processes: - preferred_term: mRNA export from nucleus term: id: GO:0006406 label: mRNA export from nucleus locations: - preferred_term: nuclear speck term: id: GO:0016607 label: nuclear speck role_description: >- Packages the spliced mRNA into an export-competent mRNP and provides the binding surfaces (ALYREF, THOC5, CHTOP) that recruit and activate NXF1. The nuclear speck location reflects the colocalisation of THO and ALYREF-NXF1 contacts with speckle domains. evidence: - source_id: PMID:15998806 statement: Human THO colocalises with splicing factors in nuclear speckles. supporting_text: We also show that the human THO complex colocalizes with splicing factors in nuclear speckle domains in vivo. - order: 2 role: handover of the mRNA to the NXF1-NXT1 export receptor node: id: nxf1_nxt1_loading label: NXF1-NXT1 export receptor loading module_type: BIOLOGICAL_PROCESS description: >- NXF1 keeps its own N-terminal RNA-binding domain closed by an intramolecular interaction. Contact with ALYREF and THOC5 opens it, the mRNA is handed from ALYREF to NXF1, and UAP56 leaves the complex. NXF1 binds mRNA directly through an arginine-rich motif, and its C-terminal NTF2-like domain, heterodimerised with NXT1 (p15), and its UBA domain then bind FG repeats for passage through the pore. evidence: - source_id: PMID:22893130 statement: ALYREF and THOC5 open NXF1 and license it to bind mRNA. supporting_text: When the TREX subunits Aly and Thoc5 make contact with Nxf1, Nxf1 is driven into an open conformation, exposing its RNA-binding domain, allowing RNA binding. - source_id: Reactome:R-HSA-159101 statement: Reactome reaction for the handover from TREX to NXF1-NXT1. supporting_text: The mRNA is transferred from ALYREF of the TREX complex to NXF1 (TAP) of the NXF1:NXT1 export complex annotons: - id: nxf1_nxt1_receptor label: NXF1-NXT1 mRNA export receptor participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: NXF1-NXT1 (TAP-p15) heterodimer term: id: GO:0042272 label: nuclear RNA export factor complex active_units: - id: nxf1 label: NXF1 (TAP) role: mRNA-binding export receptor that engages FG-nucleoporins participant: selector_type: GENE_PRODUCT gene_product: preferred_term: NXF1 term: id: UniProtKB:Q9UBU9 label: Nuclear RNA export factor 1 function: preferred_term: mRNA binding term: id: GO:0003729 label: mRNA binding evidence: - source_id: PMID:18364396 statement: TAP binds mRNA in vivo through an N-terminal arginine-rich motif, required for export. supporting_text: we show that TAP binds mRNA in vivo by an arginine-rich motif in its N-terminal domain. - source_id: PMID:9660949 statement: TAP is the human Mex67p homolog and an mRNA export mediator. supporting_text: Thus, TAP, like its yeast homolog Mex67p, is a bona fide mRNA nuclear export mediator. - id: nxt1 label: NXT1 (p15) role: NTF2-related heterodimerisation partner of NXF1 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: NXT1 term: id: UniProtKB:Q9UKK6 label: NTF2-related export protein 1 evidence: - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0001587.yaml statement: RGD record text for the heterodimer. supporting_text: Nxf1 acts as a heterodimer in partnership with Nxt1. processes: - preferred_term: mRNA export from nucleus term: id: GO:0006406 label: mRNA export from nucleus role_description: >- The export receptor for bulk mRNA: it binds the handed-over mRNA and moves with it through the pore. GO has no molecular-function term for an mRNA export receptor (GO:0140142 nucleocytoplasmic carrier activity is do-not-annotate and its only export child is the protein NES receptor term), so NXF1 carries mRNA binding and NXT1 no GO function. - order: 3 role: delivery of NXF1-bound mRNPs to the nuclear basket by TREX-2 optional: true node: id: trex2_docking label: TREX-2 at the nuclear basket module_type: BIOLOGICAL_PROCESS description: >- GANP (MCM3AP), with ENY2 and PCID2, forms the human TREX-2 complex, which sits stably on the nuclear basket through NUP153 and TPR. The FG-motif N-terminal region of GANP binds the FG-binding domain of NXF1, and GANP depletion traps mRNPs and NXF1 in nuclear foci, so TREX-2 is modelled as the step that hands NXF1-mRNPs to the pore. It is marked optional because its loss slows rather than abolishes export, and because TREX-2 knockdown phenocopies basket nucleoporins rather than NXF1. evidence: - source_id: PMID:20005110 statement: GANP is required for efficient mRNP export and NXF1 recruitment to NPCs. supporting_text: Here, we show that mammalian cells require GANP (germinal center-associated nuclear protein) for efficient mRNP nuclear export and for efficient recruitment of NXF1 to NPCs. - source_id: PMID:23591820 statement: Human TREX-2 is stably bound to the NPC basket via NUP153 and TPR. supporting_text: Moreover, the association of TREX-2 with the NPC requires the basket nucleoporins NUP153 and TPR, but is independent of transcription. annotons: - id: trex2_complex label: TREX-2 complex participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: transcription export complex 2 (TREX-2) term: id: GO:0070390 label: transcription export complex 2 active_units: - id: mcm3ap label: GANP (MCM3AP) role: TREX-2 scaffold whose FG-motif region binds NXF1 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: MCM3AP term: id: UniProtKB:O60318 label: Germinal-center associated nuclear protein function: preferred_term: NXF1 binding and transfer of NXF1-mRNPs to the NPC (no GO molecular function asserted) evidence: - source_id: PMID:20005110 statement: The GANP FG-motif region binds the NXF1 FG-binding domain. supporting_text: The GANP N-terminal region that contains FG motifs interacts with the NXF1 FG-binding domain. - id: eny2 label: ENY2 role: TREX-2 subunit shared with the SAGA deubiquitinase module participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ENY2 term: id: UniProtKB:Q9NPA8 label: Transcription and mRNA export factor ENY2 - id: pcid2 label: PCID2 role: TREX-2 PCI-domain subunit (Thp1 homolog) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PCID2 term: id: UniProtKB:Q5JVF3 label: PCI domain-containing protein 2 processes: - preferred_term: mRNA export from nucleus term: id: GO:0006406 label: mRNA export from nucleus role_description: >- Docks on the nuclear basket and passes NXF1-bound mRNPs to the pore. None of the three subunits has an experimental GO molecular function for this role (GANP's IDA functions are its MCM3 acetyltransferase activity, ENY2's is transcription coactivator activity in SAGA), so only GANP carries a free-text function. - order: 4 role: translocation of the mRNP through the nuclear pore channel node: id: npc_translocation label: Translocation through the nuclear pore complex module_type: TRANSPORT_STEP description: >- NXF1-NXT1 carries the mRNP through the central channel by binding FG repeats of the channel, basket and cytoplasmic nucleoporins. The pore is modelled by two annotons: the FG-nucleoporins that the receptor contacts, and the Nup107-160 (Y) complex that forms the outer rings of the scaffold, whose importance for mRNA export RGD records as conserved. The NPC is a shared transport organelle used by all karyopherin routes; it is included here as the structural step mRNA export depends on, not as an mRNA-specific machine. evidence: - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0001587.yaml statement: RGD record text on FG and non-FG nucleoporins in receptor passage. supporting_text: Several FG-NUPs and non-FG-NUPs are required for transport through NPC via specific interactions they establish with the transport receptors. - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0001587.yaml statement: RGD record text on the Y-complex. supporting_text: 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). annotons: - id: fg_nucleoporins label: FG-nucleoporins contacted by NXF1-NXT1 participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: nuclear pore FG-nucleoporins (central channel and basket) term: id: GO:0005643 label: nuclear pore active_units: - id: nup62 label: NUP62 role: central-channel FG-nucleoporin participant: selector_type: GENE_PRODUCT gene_product: preferred_term: NUP62 term: id: UniProtKB:P37198 label: Nuclear pore glycoprotein p62 function: preferred_term: structural constituent of nuclear pore term: id: GO:0017056 label: structural constituent of nuclear pore - id: nup54 label: NUP54 role: central-channel FG-nucleoporin participant: selector_type: GENE_PRODUCT gene_product: preferred_term: NUP54 term: id: UniProtKB:Q7Z3B4 label: Nucleoporin p54 function: preferred_term: structural constituent of nuclear pore term: id: GO:0017056 label: structural constituent of nuclear pore - id: nup58 label: NUP58 role: central-channel FG-nucleoporin participant: selector_type: GENE_PRODUCT gene_product: preferred_term: NUP58 term: id: UniProtKB:Q9BVL2 label: Nucleoporin p58/p45 function: preferred_term: structural constituent of nuclear pore term: id: GO:0017056 label: structural constituent of nuclear pore - id: nup98 label: NUP98 role: mobile GLFG-nucleoporin, also important for the CRM1 routes participant: selector_type: GENE_PRODUCT gene_product: preferred_term: NUP98 term: id: UniProtKB:P52948 label: Nuclear pore complex protein Nup98-Nup96 function: preferred_term: structural constituent of nuclear pore term: id: GO:0017056 label: structural constituent of nuclear pore - id: nup153 label: NUP153 role: basket FG-nucleoporin that also anchors TREX-2 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: NUP153 term: id: UniProtKB:P49790 label: Nuclear pore complex protein Nup153 function: preferred_term: structural constituent of nuclear pore term: id: GO:0017056 label: structural constituent of nuclear pore processes: - preferred_term: mRNA export from nucleus term: id: GO:0006406 label: mRNA export from nucleus role_description: >- Form the selective FG-repeat meshwork through which the NXF1-NXT1-bound mRNP passes. NUP214, the cytoplasmic FG-nucleoporin, is modelled in the remodelling step because its mRNA-export role is to anchor DDX19. evidence: - source_id: PMID:20005110 statement: NXF1 crosses the central channel through transient FG-nucleoporin contacts. supporting_text: mediates translocation through the central NPC transport channel via transient interactions with FG nucleoporins - id: y_complex label: Nup107-160 (Y) complex scaffold participant: selector_type: PROTEIN_COMPLEX protein_complex: preferred_term: Nup107-160 complex (Y-complex) term: id: GO:0031080 label: nuclear pore outer ring active_units: - id: nup107 label: NUP107 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: NUP107 term: id: UniProtKB:P57740 label: Nuclear pore complex protein Nup107 function: preferred_term: structural constituent of nuclear pore term: id: GO:0017056 label: structural constituent of nuclear pore - id: nup133 label: NUP133 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: NUP133 term: id: UniProtKB:Q8WUM0 label: Nuclear pore complex protein Nup133 function: preferred_term: structural constituent of nuclear pore term: id: GO:0017056 label: structural constituent of nuclear pore - id: nup160 label: NUP160 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: NUP160 term: id: UniProtKB:Q12769 label: Nuclear pore complex protein Nup160 function: preferred_term: structural constituent of nuclear pore term: id: GO:0017056 label: structural constituent of nuclear pore - id: nup85 label: NUP85 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: NUP85 term: id: UniProtKB:Q9BW27 label: Nuclear pore complex protein Nup85 function: preferred_term: structural constituent of nuclear pore term: id: GO:0017056 label: structural constituent of nuclear pore - id: nup37 label: NUP37 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: NUP37 term: id: UniProtKB:Q8NFH4 label: Nucleoporin Nup37 - id: nup43 label: NUP43 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: NUP43 term: id: UniProtKB:Q8NFH3 label: Nucleoporin Nup43 - id: sec13 label: SEC13 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SEC13 term: id: UniProtKB:P55735 label: Protein SEC13 homolog - id: seh1l label: SEH1L participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SEH1L term: id: UniProtKB:Q96EE3 label: Nucleoporin SEH1 role_description: >- The outer-ring scaffold that holds the pore open and positions the FG layer. It is context for mRNA export rather than a receptor-contacting activity, so no mRNA-export process is asserted on it here. - order: 5 role: mRNP remodelling and release at the cytoplasmic filaments node: id: cytoplasmic_remodelling label: DDX19-GLE1-IP6 remodelling at the cytoplasmic face module_type: BIOLOGICAL_PROCESS description: >- As the mRNP emerges, the DEAD-box ATPase DDX19 (Dbp5), held on the cytoplasmic filaments by NUP214, is activated by GLE1 bound to inositol hexakisphosphate (IP6). GLE1-IP6 stimulates RNA-dependent ATP hydrolysis and RNA release, and NUP214 binding is mutually exclusive with RNA binding, so the cycle strips export factors (NXF1, ALYREF) from the mRNA and keeps export directional. The mechanism was worked out mainly in yeast (Dbp5, Gle1, Nup159) and with crystal structures of the human DDX19-NUP214 pair. evidence: - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0001587.yaml statement: RGD record text for the remodelling step. supporting_text: Ddx19 is specifically bound to Nup214 and its RNA-dependent ATPase activity relies on Gle1-IP6 stimulation and Nup214-triggered ADP release. - source_id: PMID:16783363 statement: Gle1 and IP6 together stimulate the RNA-dependent ATPase of Dbp5 (yeast). supporting_text: Here, we show that Gle1 and InsP6 act together to stimulate the RNA-dependent ATPase activity of the essential DEAD-box protein Dbp5. - source_id: PMID:21441902 statement: Structural basis of DDX19/Dbp5 activation by Gle1-IP6 and its NUP214/Nup159 anchor. supporting_text: Dbp5 is localized to the NPC via an interaction with Nup159 (NUP214 in vertebrates) and is locally activated there by Gle1 together with the small-molecule inositol hexakisphosphate (InsP(6)). - source_id: Reactome:R-HSA-75098 statement: Reactome reaction for release of export factors at the cytosolic face. supporting_text: At the end of this reaction, 1 molecule of 'THOC4(Aly/Ref)', 1 molecule of 'Mature mRNP Complex', 1 molecule of 'SRm160', and 1 molecule of 'TAP' are present. annotons: - id: ddx19b_remodelling label: DDX19B RNA-dependent ATPase remodelling the mRNP participant: selector_type: GENE_PRODUCT gene_product: preferred_term: DDX19B term: id: UniProtKB:Q9UMR2 label: ATP-dependent RNA helicase DDX19B function: preferred_term: RNA helicase activity term: id: GO:0003724 label: RNA helicase activity processes: - preferred_term: mRNA export from nucleus term: id: GO:0006406 label: mRNA export from nucleus role_description: >- The DEAD-box remodelling ATPase of the cytoplasmic face. GO:0003724 is DDX19B's GOA function (IBA), with GO:0016887 ATP hydrolysis activity by EXP; DDX19B is not a processive helicase in this role, and the remodelling it performs is RNA release coupled to ATP hydrolysis. The paralog DDX19A is not modelled (see notes). evidence: - source_id: PMID:19219046 statement: Human DBP5 binds RNA or NUP214, mutually exclusively; NUP214 lowers its RNA binding and ATPase. supporting_text: Using in vitro assays, we demonstrate that NUP214 decreases both the RNA binding and ATPase activities of DBP5. - id: gle1_activator label: GLE1-IP6 activator of DDX19 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GLE1 term: id: UniProtKB:Q53GS7 label: mRNA export factor GLE1 function: preferred_term: inositol hexakisphosphate binding term: id: GO:0000822 label: inositol hexakisphosphate binding processes: - preferred_term: mRNA export from nucleus term: id: GO:0006406 label: mRNA export from nucleus role_description: >- Binds IP6 and, as GLE1-IP6, activates DDX19 by stimulating ATP hydrolysis and RNA release. GO:0000822 is GLE1's GOA function (IBA); GLE1 has no annotation to GO:0001671 ATPase activator activity, which would describe the activation itself and is a candidate for upstream annotation (yeast Gle1 evidence, PMID:16783364). evidence: - source_id: PMID:16783364 statement: Gle1 binds IP6 directly and IP6 potentiates Gle1 stimulation of Dbp5 (yeast). supporting_text: Interestingly, Gle1 binds directly to inositol hexakisphosphate (InsP6) and InsP6 potentiates the Gle1-mediated stimulation of Dbp5. - id: nup214_anchor label: NUP214 cytoplasmic-filament anchor of DDX19 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: NUP214 term: id: UniProtKB:P35658 label: Nuclear pore complex protein Nup214 function: preferred_term: structural constituent of nuclear pore term: id: GO:0017056 label: structural constituent of nuclear pore processes: - preferred_term: mRNA export from nucleus term: id: GO:0006406 label: mRNA export from nucleus role_description: >- Cytoplasmic-filament FG-nucleoporin that concentrates DDX19 at the pore exit and triggers ADP release. GO:0017056 (IBA) is its structural role; its binding of DDX19 has no more specific GO function term. evidence: - source_id: PMID:19219046 statement: Crystal structure of human DBP5 bound to NUP214. supporting_text: We have determined the crystal structures of human DBP5 bound to RNA and AMPPNP, and bound to the cytoplasmic nucleoporin NUP214. - order: 6 role: CRM1 (XPO1)-dependent export of specific mRNA classes optional: true node: id: crm1_mrna_export label: CRM1 route for specific mRNAs module_type: BIOLOGICAL_PROCESS description: >- A minority of mRNAs are exported by the karyopherin CRM1 (XPO1) instead of NXF1. Because mRNA carries no nuclear export signal, an NES-bearing RNA-binding adaptor links each mRNA class to CRM1. RanGTP is required for CRM1 to bind cargo in the nucleus, and on the cytoplasmic side RanGAP1, with RanBP1 and RanBP2, stimulates Ran GTP hydrolysis to release the cargo. The route is optional: it is not required for bulk export, and its adaptors define alternative cargo classes rather than successive steps. evidence: - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0001587.yaml statement: RGD record text for cargo release in the CRM1 routes. supporting_text: The CRM1-mediated export routes share in common the cargo release, dependent upon RanGTP hydrolysis, which is coordinated by Ranbp1 and Ranbp2, and RanGAP. - source_id: PMID:19262567 statement: The eIF4E export RNP is distinct from the bulk NXF1/ALYREF pathway. supporting_text: The eIF4E export RNP is distinct in composition from the bulk mRNA export pathway, in that eIF4E- and eIF4E-sensitive mRNAs do not associate with general mRNA export factors such as TAP/NXF1 or REF/Aly. annotons: - id: xpo1_receptor label: CRM1 (XPO1) export receptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: XPO1 term: id: UniProtKB:O14980 label: Exportin-1 function: preferred_term: nuclear export signal receptor activity term: id: GO:0005049 label: nuclear export signal receptor activity processes: - preferred_term: mRNA export from nucleus term: id: GO:0006406 label: mRNA export from nucleus role_description: >- Binds the NES of the mRNA-specific adaptor together with RanGTP and carries the adaptor-mRNA complex through the pore. GO:0005049 is supported by IDA/IMP in GOA and is the function the human FMRP export GO-CAM uses. gocam_associations: - model: gomodel:63894f2500001748 activity: gomodel:63894f2500001748/63894f2500001783 title: XPO1 nuclear export signal receptor activity (GO:0005049), part of GO:0006406 - id: ran_gtpase label: Ran GTPase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RAN term: id: UniProtKB:P62826 label: GTP-binding nuclear protein Ran function: preferred_term: GTPase activity term: id: GO:0003924 label: GTPase activity role_description: >- RanGTP is needed for CRM1 to bind cargo; its GTP hydrolysis at the cytoplasmic face releases the cargo. GO:0003924 is supported by IDA in GOA. - id: rangap1 label: RanGAP1 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RANGAP1 term: id: UniProtKB:P46060 label: Ran GTPase-activating protein 1 function: preferred_term: GTPase activator activity term: id: GO:0005096 label: GTPase activator activity role_description: >- Stimulates Ran GTP hydrolysis on the cytoplasmic side, dissociating the export complex (IDA in GOA). - id: ranbp1 label: RanBP1 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RANBP1 term: id: UniProtKB:P43487 label: Ran-specific GTPase-activating protein function: preferred_term: RanGTP release from CRM1 complexes as RanGAP co-activator (no GO molecular function asserted) role_description: >- Binds RanGTP in the cytoplasm and makes it accessible to RanGAP1. Its GOA functions (GDP-dissociation inhibitor activity by IMP, small GTPase binding by TAS) do not describe this co-activation, so none is asserted. - id: ranbp2 label: RanBP2 (NUP358) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RANBP2 term: id: UniProtKB:P49792 label: E3 SUMO-protein ligase RanBP2 function: preferred_term: cytoplasmic-filament docking of RanGTP-CRM1 export complexes (no GO molecular function asserted) role_description: >- Cytoplasmic-filament nucleoporin whose Ran-binding domains capture RanGTP-CRM1 complexes and which holds SUMO-modified RanGAP1 at the pore. Its experimental GO functions are SUMO ligase activity and small GTPase binding, neither of which is the role in mRNA export. variant_sets: - id: crm1_mrna_adaptor label: CRM1 adaptor for a specific mRNA class axis: cargo class (cis-element or modification recognised by the adaptor) variant_kind: ROUTE selection: ONE_OR_MORE variants: - id: lrpprc_eif4e_route label: eIF4E-sensitivity element mRNAs (LRPPRC with eIF4E) module_type: BIOLOGICAL_PROCESS annotons: - id: eif4e_export label: eIF4E cap binding on 4E-SE mRNAs participant: selector_type: GENE_PRODUCT gene_product: preferred_term: EIF4E term: id: UniProtKB:P06730 label: Eukaryotic translation initiation factor 4E function: preferred_term: RNA 7-methylguanosine cap binding term: id: GO:0000340 label: RNA 7-methylguanosine cap binding role_description: >- Nuclear eIF4E binds the cap of mRNAs carrying the 4E-SE and is exported with them (GO:0000340 IDA in GOA). - id: lrpprc_export label: LRPPRC bridging eIF4E, 4E-SE mRNA and CRM1 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: LRPPRC term: id: UniProtKB:P42704 label: Leucine-rich PPR motif-containing protein, mitochondrial function: preferred_term: mRNA binding term: id: GO:0003729 label: mRNA binding role_description: >- Binds 4E-SE mRNAs and eIF4E and recruits CRM1. GO:0003729 (IDA) is LRPPRC's core function in its gene review, where it is attached to mitochondrial mRNA metabolism; the nuclear export role involves a minor nuclear fraction and is kept non-core there. evidence: - source_id: PMID:19262567 statement: LRPPRC associates with 4E-SE mRNAs and alters their export. supporting_text: This protein associates with mRNAs containing the eIF4E-sensitivity element (4E-SE), and its overexpression alters the nuclear export of several eIF4E-sensitive mRNAs. - id: hur_are_route label: AU-rich element mRNAs (HuR with pp32 and APRIL) module_type: BIOLOGICAL_PROCESS annotons: - id: elavl1_export label: HuR (ELAVL1) binding of ARE mRNAs participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ELAVL1 term: id: UniProtKB:Q15717 label: ELAV-like protein 1 function: preferred_term: mRNA 3'-UTR AU-rich region binding term: id: GO:0035925 label: mRNA 3'-UTR AU-rich region binding role_description: >- Binds the AU-rich element of the cargo mRNA (core function in the ELAVL1 gene review) and links it, through pp32 and APRIL, to CRM1. evidence: - source_id: Reactome:R-HSA-450387 statement: Reactome reaction for HuR binding the CRM1 export machinery. supporting_text: HuR interacts with SETalpha (Template activating factor 1), SETbeta (CAN/Nup214), APRIL, pp32, and the nuclear export factor CRM1. - id: anp32a_export label: pp32 (ANP32A) NES-bearing HuR ligand participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ANP32A term: id: UniProtKB:P39687 label: Acidic leucine-rich nuclear phosphoprotein 32 family member A function: preferred_term: bridging HuR to CRM1 (no GO molecular function asserted) - id: anp32b_export label: APRIL (ANP32B) NES-bearing HuR ligand participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ANP32B term: id: UniProtKB:Q92688 label: Acidic leucine-rich nuclear phosphoprotein 32 family member B function: preferred_term: bridging HuR to CRM1 (no GO molecular function asserted) evidence: - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0001587.yaml statement: RGD record text for the LRPPRC, HuR and NXF3 CRM1 adaptor routes. supporting_text: 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 - id: nxf3_route label: NXF3-dependent RNA export module_type: BIOLOGICAL_PROCESS annotons: - id: nxf3_export label: NXF3 RNA-binding adaptor with a CRM1-dependent NES participant: selector_type: GENE_PRODUCT gene_product: preferred_term: NXF3 term: id: UniProtKB:Q9H4D5 label: Nuclear RNA export factor 3 function: preferred_term: RNA binding term: id: GO:0003723 label: RNA binding role_description: >- An NXF-family RNA-binding protein that lacks the NPC-binding domain of NXF1 and instead uses its own CRM1-dependent NES. Its endogenous mRNA cargoes are not defined (testis-enriched expression). evidence: - source_id: PMID:11545741 statement: NXF3 exports RNA through CRM1, not through the NXF1 pathway. supporting_text: NXF3 contains a novel Crm1-dependent nuclear export signal that compensates in cis for the loss of the nuclear pore targeting domain. - id: fmr1_m6a_route label: N6-methyladenosine-marked mRNAs (FMRP) module_type: BIOLOGICAL_PROCESS annotons: - id: fmr1_export label: FMRP m6A reader recruiting CRM1 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: FMR1 term: id: UniProtKB:Q06787 label: Fragile X messenger ribonucleoprotein 1 function: preferred_term: N6-methyladenosine-containing RNA reader activity term: id: GO:1990247 label: N6-methyladenosine-containing RNA reader activity processes: - preferred_term: mRNA export from nucleus term: id: GO:0006406 label: mRNA export from nucleus role_description: >- Not in the RGD gene list; added because the only production human mRNA export GO-CAM models FMRP as a CRM1-dependent m6A-mRNA export adaptor. gocam_associations: - model: gomodel:63894f2500001748 activity: gomodel:63894f2500001748/63894f2500001774 title: FMR1 N6-methyladenosine-containing RNA reader activity (GO:1990247), part of GO:0006406 connections: - source: trex_assembly target: nxf1_nxt1_loading connection_type: PRECEDES description: >- TREX (ALYREF, THOC5, CHTOP) recruits NXF1, opens its RNA-binding domain and hands the mRNA over to it. - source: nxf1_nxt1_loading target: npc_translocation connection_type: PRECEDES description: The mRNA-loaded NXF1-NXT1 engages FG-nucleoporins and crosses the pore. - source: trex2_docking target: npc_translocation connection_type: POSITIVELY_REGULATES description: >- TREX-2 on the basket binds NXF1 and promotes delivery of NXF1-mRNPs to the pore. - source: npc_translocation target: cytoplasmic_remodelling connection_type: PRECEDES description: >- The emerging mRNP is remodelled by DDX19-GLE1-IP6 at the cytoplasmic filaments, which releases NXF1 and ALYREF for recycling. - source: crm1_mrna_export target: npc_translocation connection_type: PRECEDES description: >- Adaptor-CRM1-RanGTP-mRNA complexes cross the same pore; their release depends on Ran GTP hydrolysis rather than on DDX19. knowledge_gaps: - gap_statement: >- How the cytoplasmic DDX19-GLE1-IP6 cycle releases NXF1 and ALYREF from the mRNP in human cells is not established. The activation mechanism was defined with yeast Dbp5, Gle1 and Nup159, and the human DDX19-NUP214 structures show that NUP214 and RNA binding are mutually exclusive, but which human mRNP proteins DDX19 displaces, how many ATP cycles one mRNP needs, and whether human GLE1 requires IP6 to the same degree are not known. boundary: >- The remodelling step is modelled with DDX19B, GLE1 and NUP214 as separate annotons, with the release of export factors stated in prose rather than as a has-output relation. gap_kind: - BIOLOGY status: OPEN significance: >- This step is what makes export directional and recycles the export factors, and human GLE1 mutations cause lethal congenital contracture syndrome, so the human mechanism bears directly on disease interpretation. resolution: >- Reconstitution of human DDX19B ATPase and RNA release with GLE1, IP6 and NUP214 using purified human mRNPs carrying NXF1-NXT1 and ALYREF, combined with single-molecule imaging of export-factor release at the pore in cells expressing IP6-binding-deficient GLE1. provenance: - reference_id: PMID:19219046 supporting_text: These results suggest a framework for the consecutive steps leading to the release of mRNA at the final stages of nuclear export. - gap_statement: >- The share of cellular mRNA exported by CRM1 rather than NXF1, and the endogenous cargoes of NXF3, are undefined. Each CRM1 adaptor route was described with a handful of reporter or candidate mRNAs. boundary: >- The CRM1 route is an optional part, and its adaptors a ONE_OR_MORE ROUTE variant set; NXF3 is modelled without named cargo. gap_kind: - BIOLOGY status: OPEN significance: >- Whether the CRM1 route is a minor specialised pathway or a regulated switch for whole mRNA classes (for example in proliferation through eIF4E, or in stress through HuR) decides whether it should be treated as part of core mRNA export or as regulation. resolution: >- Transcriptome-wide nuclear/cytoplasmic fractionation sequencing after acute, degron-mediated depletion of NXF1 versus XPO1 (and of each adaptor), with CLIP of NXF3 in testis-derived cells to identify its cargoes. provenance: - reference_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0001587.yaml supporting_text: 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.