Alternative titles; symbols
HGNC Approved Gene Symbol: NXF1
Cytogenetic location: 11q12.3 Genomic coordinates (GRCh38): 11:62,792,130-62,805,440 (from NCBI)
Segref et al. (1997) identified a yeast gene, MEX67, that encodes a factor essential for nuclear mRNA export. The Mex67 protein is found at the nuclear pores, can be UV-crosslinked to polyadenylated RNA, and interacts with a putative RNA-binding protein in a yeast 2-hybrid screen. Thus, Segref et al. (1997) suggested that the Mex67 protein participates directly in the export of mRNA from the nucleus to the cytoplasm. They reported that the Mex67 protein is homologous to the human 'tip-associated protein' (TAP).
The 'tyrosine kinase-interacting protein' (Tip) of herpesvirus saimiri blocks LCK (153390)-mediated signal transduction and is essential for primary T cell immortalization and for lymphoma induction in vivo. Using the yeast 2-hybrid system to identify factors that associate with Tip, Yoon et al. (1997) cloned a cDNA encoding 'tip-associated protein' (TAP). The predicted 560-amino acid TAP protein migrates as a 65-kD protein by SDS-PAGE. Northern blot analysis indicated that TAP was expressed as 2.5- and 4.4-kb mRNAs in all tissues tested. Expression of Tip and TAP in Jurkat-T cells induced cell aggregation, which was likely caused by the upregulated surface expression of lymphocyte adhesion molecules, and NF-kappa-B (164011, 164012) activity. Therefore, Yoon et al. (1997) suggested that TAP is an important cellular mediator of Tip function in T-cell transformation by herpesvirus saimiri.
Gruter et al. (1998) reported the identification of TAP as the cellular factor that specifically binds to the CTE (constitutive transport element) of the type D retroviruses. Microinjection experiments performed in Xenopus oocytes demonstrated that TAP directly stimulates CTE-dependent export. Furthermore, TAP overcomes the mRNA export block caused by the presence of saturating amounts of CTE RNA. Thus, TAP, like its yeast homolog Mex67, is an mRNA nuclear export mediator. TAP is therefore a cellular RNA binding protein that is directly involved in the export of its target RNA.
Using binding analysis, Herold et al. (2000) showed that NXF1, NXF2 (300315), and NXF3 (300316) interact with E1BAP5 (605800), as well as with NXT1 (605811) and NXT2 (300320). The RBDs of NXF1 and NXF2, but not that of NXF3, were found to bind RNA. Only NXF1, however, could promote RNA export mediated by the constitutive transport element of simian type D retrovirus. Both NXF1 and NXF2, but not NXF3, through their C-terminal NWD loop, could bind to the nucleoporins CAN (NUP214; 114350), NUP153 (603948), and NUP62 (605815). Only NXF1 could bind to NUP98 (601021). CAT reporter and Western blot assays showed that coexpression of NXF1 or NXF2, but not NXF3, with NXT1 or NXT2 activated CAT expression, suggesting that under these conditions NXF1 can also stimulate RNA export. The LRRs and NTF2 (605813)-like domains are required for export activity.
Shamsher et al. (2002) found that transportin-2 (603002) forms complexes with TAP that strictly depend on the presence of RanGTP. The data supported the conclusion that transportin-2 participates directly in the export of a large proportion of cellular mRNAs, and that TAP connects transportin-2 to mRNAs to be exported.
Li et al. (2006) showed that the TAP gene contains a functional constitutive transport element (CTE) in its alternatively spliced intron 10. TAP mRNA containing this intron is exported to the cytoplasm and is present in polyribosomes. A small TAP protein is encoded by this mRNA and can be detected in human and monkey cells. Li et al. (2006) concluded that TAP regulates expression of its own intron-containing RNA through a CTE-mediated mechanism, and that CTEs are likely to be important elements that facilitate efficient expression of mammalian mRNAs with retained introns.
FMRP (FMR1; 309550) is a nucleocytoplasmic shuttling RNA-binding protein that participates in mRNA transport and translational control. Using immunoprecipitation analysis and quantitative real-time RT-PCR, Zhang et al. (2007) showed that Fmrp and Nxf2 were present in Nxf1 mRNA-containing ribonucleoprotein particles in cultured mouse neuronal cells. Expression of Nxf2 led to destabilization of Nxf1 mRNA, and this effect was abolished when Fmrp expression was reduced by small interfering RNA. Zhang et al. (2007) concluded that FMRP and NXF2 collaborate to destabilize NXF1 mRNA.
Zander et al. (2016) showed in yeast that cellular stress induces the dissociation of Mex67 and its adaptor proteins from regular mRNAs to prevent general mRNA export. At the same time, heat-shock mRNAs are rapidly exported in association with Mex67, without the need for adaptors. The immediate cotranscriptional loading of Mex67 onto heat-shock mRNAs involves Hsf1 (140580), a heat-shock transcription factor that binds to heat-shock promoter elements in stress-responsive genes. An important difference between the export modes is that adaptor protein-bound mRNAs undergo quality control, whereas stress-specific transcripts do not. In fact, regular mRNAs are converted into uncontrolled stress-responsive transcripts if expressed under the control of a heat-shock promoter, suggesting that whether an mRNA undergoes quality control is encrypted therein. Under normal conditions, Mex67 adaptor proteins are recruited for RNA surveillance, with only quality-controlled mRNAs allowed to associate with Mex67 and leave the nucleus. Thus, Zander et al. (2016) concluded that at the cost of error-free mRNA formation, heat-shock mRNAs are exported and translated without delay, allowing cells to survive extreme situations.
Herold et al. (2000) determined that the NXF1 gene contains at least 21 exons.
Using genomic sequence analysis, Herold et al. (2000) mapped the NXF1 gene to chromosome 11.
Gross (2014) mapped the NXF1 gene to chromosome 11q12.3 based on an alignment of the NXF1 sequence (GenBank AF112880) with the genomic sequence (GRCh37).
Hamilton et al. (1997) mapped the mouse Nxf1 gene to proximal chromosome 19.
In mice, the modifier-of-vibrator-1 locus (Mvb1) controls levels of correctly processed mRNA from genes mutated by endogenous retrovirus insertions into introns, including the Pitpn(vb) (600174) tremor mutation and the Eya1(BOR) (601653) model of human branchiootorenal syndrome. By positional complementation cloning, Floyd et al. (2003) identified Mvb1 as the nuclear export factor Nxf1, providing an unexpected link between the mRNA export receptor and pre-mRNA processing. Population structure of the suppressive allele in wild Mus musculus castaneus suggested selective advantage.
Intracisternal A particles (IAPs) are a source of new mutations and polymorphisms, particularly in mouse strains. These insertional mutations can be suppressed by Nxf1, notably by the wildtype allele in M. musculus castaneus, termed Nxf1CAST. Concepcion et al. (2015) showed that Nxf1CAST could modify gene expression phenotypes at several loci in the C57Bl/6 mouse reference genome that contain IAP sequences in their introns, including Adamts13 (604134). Nxf1CAST restored correct splicing between exons 24 and 25 of Adamts13. Nxf1 genotype did not influence alternative splicing at non-IAP sites. CRISPR/Cas9-mediated genome editing showed that a C-terminal glu610-to-gly (E610G) substitution in the C-terminal UBA (see 608129)-like domain of Nxf1 was sufficient to recreate a quantitative genetic modifier in a coisogenic background and to enhance expression of full-length mRNA at multiple loci.
Concepcion, D., Ross, K. D., Hutt, K. R., Yeo, G. W., Hamilton, B. A. Nxf1 natural variant E610G is a semi-dominant suppressor of IAP-induced RNA processing defects. PLoS Genet. 11: e1005123, 2015. Note: Electronic Article. [PubMed: 25835743] [Full Text: https://doi.org/10.1371/journal.pgen.1005123]
Floyd, J. A., Gold, D. A., Concepcion, D., Poon, T. H., Wang, X., Keithley, E., Chen, D., Ward, E. J., Chinn, S. B., Friedman, R. A., Yu, H.-T., Moriwaki, K., Shiroishi, T., Hamilton, B. A. A natural allele of Nxf1 suppresses retrovirus insertional mutations. Nature Genet. 35: 221-228, 2003. [PubMed: 14517553] [Full Text: https://doi.org/10.1038/ng1247]
Gross, M. B. Personal Communication. Baltimore, Md. 4/21/2014.
Gruter, P., Tabernero, C., von Kobbe, C., Schmitt, C., Saavedra, C., Bachi, A., Wilm, M., Felber, B. K., Izaurralde, E. TAP, the human homolog of Mex67p, mediates CTE-dependent RNA export from the nucleus. Molec. Cell 1: 649-659, 1998. [PubMed: 9660949] [Full Text: https://doi.org/10.1016/s1097-2765(00)80065-9]
Hamilton, B. A., Smith, D. J., Mueller, K. L., Kerrebrock, A. W., Bronson, R. T., van Berkel, V., Daly, M. J., Kruglyak, L., Reeve, M. P., Nemhauser, J. L., Hawkins, T. L., Rubin, E. M., Lander, E. S. The vibrator mutation causes neurodegeneration via reduced expression of PITP-alpha: positional complementation cloning and extragenic suppression. Neuron 18: 711-722, 1997. [PubMed: 9182797] [Full Text: https://doi.org/10.1016/s0896-6273(00)80312-8]
Herold, A., Suyama, M., Rodrigues, J. P., Braun, I. C., Kutay, U., Carmo-Fonseca, M., Bork, P., Izaurralde, E. TAP (NXF1) belongs to a multigene family of putative RNA export factors with a conserved modular architecture. Molec. Cell. Biol. 20: 8996-9008, 2000. [PubMed: 11073998] [Full Text: https://doi.org/10.1128/MCB.20.23.8996-9008.2000]
Li, Y., Bor, Y., Misawa, Y., Xue, Y., Rekosh, D., Hammarskjold, M.-L. An intron with a constitutive transport element is retained in a Tap messenger RNA. Nature 443: 234-237, 2006. [PubMed: 16971948] [Full Text: https://doi.org/10.1038/nature05107]
Segref, A., Sharma, K., Doye, V., Hellwig, A., Huber, J., Luhrmann, R., Hurt, E. Mex67p, a novel factor for nuclear mRNA export, binds to both poly(A)+ RNA and nuclear pores. EMBO J. 16: 3256-3271, 1997. [PubMed: 9214641] [Full Text: https://doi.org/10.1093/emboj/16.11.3256]
Shamsher, M. K., Ploski, J., Radu, A. Karyopherin beta-2B participates in mRNA export from the nucleus. Proc. Nat. Acad. Sci. 99: 14195-14199, 2002. [PubMed: 12384575] [Full Text: https://doi.org/10.1073/pnas.212518199]
Yoon, D.-W., Lee, H., Seol, W., DeMaria, M., Rosenzweig, M., Jung, J. U. Tap: a novel cellular protein that interacts with Tip of herpesvirus saimiri and induces lymphocyte aggregation. Immunity 6: 571-582, 1997. [PubMed: 9175835] [Full Text: https://doi.org/10.1016/s1074-7613(00)80345-3]
Zander, G., Hackmann, A., Bender, L., Becker, D., Lingner, T., Salinas, G., Krebber, H. mRNA quality control is bypassed for immediate export of stress-responsive transcripts. Nature 540: 593-596, 2016. [PubMed: 27951587] [Full Text: https://doi.org/10.1038/nature20572]
Zhang, M., Wang, Q., Huang, Y. Fragile X mental retardation protein FMRP and the RNA export factor NXF2 associate with and destabilize Nxf1 mRNA in neuronal cells. Proc. Nat. Acad. Sci. 104: 10057-10062, 2007. [PubMed: 17548835] [Full Text: https://doi.org/10.1073/pnas.0700169104]