Affinage

RAE1

mRNA export factor RAE1 · UniProt P78406

Length
368 aa
Mass
41.0 kDa
Annotated
2026-04-28
78 papers in source corpus 36 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAE1 is a WD40-repeat beta-propeller protein that functions at the nexus of mRNA nuclear export and mitotic regulation. As a seven-bladed beta-propeller, RAE1 binds the GLEBS motif of NUP98 at the nuclear pore complex, where it engages single-stranded RNA through a conserved basic groove to facilitate mRNA translocation; this same groove is competitively targeted by viral proteins including VSV M protein and SARS-CoV-2 ORF6 to block nucleocytoplasmic transport and suppress host antiviral responses (PMID:20498086, PMID:24927547, PMID:35096974). During mitosis, the RAE1–NUP98 complex inhibits APC/C-Cdh1-mediated ubiquitination of securin until the metaphase-to-anaphase transition, and RAE1 independently interacts with NuMA to convert it into a tetravalent microtubule crosslinker required for bipolar spindle assembly; haploinsufficiency of RAE1 causes chromosome missegregation and tumor susceptibility in mice (PMID:16355229, PMID:17172455, PMID:12551952). Separately, the murine RAE-1 family encodes GPI-anchored cell-surface NKG2D ligands whose expression is transcriptionally controlled by E2F, PI3K/HDAC3, and STING-IRF3 pathways and whose engagement of NKG2D activates NK cell and CD8+ T cell anti-tumor immunity (PMID:11557981, PMID:23166357, PMID:27874833).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1995 High

    Establishing that RAE1 is an essential mRNA export factor and WD40-repeat protein resolved what gene product mediates poly(A)+ RNA nuclear export in fission yeast, and revealed a dual connection to cell cycle progression.

    Evidence Temperature-sensitive rae1-1 mutant in S. pombe with FISH for poly(A)+ RNA accumulation, cell cycle analysis showing G2/M arrest

    PMID:7706287

    Open questions at the time
    • Mechanism of mRNA engagement unknown
    • Whether cell cycle arrest is direct or secondary to export block unclear
    • No metazoan data
  2. 1996 High

    Demonstration that the budding yeast homolog Gle2 localizes to NPCs and interacts with nucleoporin Nup100p established that RAE1 functions at the nuclear pore rather than in the nucleoplasm.

    Evidence Indirect immunofluorescence, NPC fractionation, and two-hybrid interaction with Nup100p in S. cerevisiae

    PMID:8970155

    Open questions at the time
    • Direct binding partner in metazoans not yet identified
    • RNA-binding activity not tested
  3. 1999 High

    Identification of NUP98 as the direct binding partner of mammalian RAE1 via a GLEBS motif, and demonstration that this interaction is required for mRNA export, established the core RAE1–NUP98 axis at the NPC.

    Evidence In vitro binding, chemical cross-linking, Xenopus oocyte microinjection with GLEBS competition blocking poly(A)+ RNA export

    PMID:10209021

    Open questions at the time
    • Structural basis of GLEBS recognition unknown
    • Whether RAE1 contacts mRNA directly unresolved
  4. 2000 Medium

    Ultrastructural evidence that RAE1 binds mRNP cargo specifically at the NPC channel — not cotranscriptionally — established it as a transient NPC-associated export factor rather than an mRNP packaging component.

    Evidence Immunoelectron microscopy on Chironomus tentans Balbiani ring mRNP at nuclear pores

    PMID:11105759

    Open questions at the time
    • Single organism (dipteran), generality to mammals not directly shown
    • Molecular contacts between RAE1 and mRNP undefined
  5. 2001 High

    Discovery that murine RAE-1 isoforms are GPI-anchored cell-surface NKG2D ligands that trigger NK cell and CD8+ T cell anti-tumor rejection established a distinct immune function for the RAE-1 gene family, separate from the nucleoporin-associated mRNA export protein.

    Evidence Tumor transfection with Rae1beta, in vivo syngeneic rejection with NK/T cell depletion; SPR and ITC measuring nanomolar NKG2D binding

    PMID:11520456 PMID:11557981

    Open questions at the time
    • Regulation of RAE-1 surface expression unknown
    • Structural basis of NKG2D–RAE-1 recognition not yet solved
    • Human ortholog functional equivalence assumed but not tested
  6. 2003 High

    Rae1 haploinsufficiency in mice revealed an essential mitotic checkpoint role separable from mRNA export: Rae1+/− mice showed chromosome missegregation and tumor susceptibility without detectable export defects, and genetic interaction with Bub3 indicated a shared spindle checkpoint pathway.

    Evidence Conditional knockout mice with chromosome segregation assay, mitotic checkpoint assay, and mRNA export measurement; Rae1/Bub3 compound haploinsufficiency

    PMID:12551952

    Open questions at the time
    • Molecular mechanism of checkpoint function unknown
    • Whether RAE1 directly participates in spindle checkpoint signaling or acts indirectly unresolved
  7. 2005 High

    Two breakthrough studies defined RAE1's mitotic mechanisms: (1) Rae1–Nup98 complex inhibits APC/C-Cdh1 ubiquitination of securin to prevent premature sister chromatid separation, and (2) Rae1 is a RanGTP/importin-beta-regulated microtubule-associated spindle assembly factor whose function requires associated RNA.

    Evidence APC ubiquitination assay and mouse haploinsufficiency genetics (securin); activity-based purification from Xenopus egg extracts with immunodepletion and microtubule dynamics assay (spindle assembly)

    PMID:15851029 PMID:16355229

    Open questions at the time
    • How securin inhibition is relieved at metaphase-anaphase transition not fully defined
    • Identity of the RNA species required for spindle assembly unknown
    • How the mRNA export and mitotic functions are temporally coordinated unclear
  8. 2005 High

    VSV M protein was shown to directly bind RAE1 and block mRNA export, with a loss-of-binding M mutant unable to inhibit export and RAE1 overexpression fully rescuing the block — establishing RAE1–NUP98 as a viral target for host gene expression shutoff.

    Evidence Co-immunoprecipitation, M protein mutant analysis, RAE1 overexpression rescue, mRNA export assay

    PMID:15629720

    Open questions at the time
    • Structural basis of M protein–RAE1 interaction unknown at this time
    • Whether other viruses exploit the same mechanism unresolved
  9. 2006 High

    RAE1 was found to interact with NuMA in a mitosis-specific manner, converting the NuMA dimer into a tetravalent microtubule crosslinker essential for bipolar spindle formation — establishing a third distinct mitotic role for RAE1.

    Evidence Mitosis-specific co-immunoprecipitation, domain mapping, reciprocal RNAi/overexpression titration of RAE1 and NuMA with spindle phenotype scoring in HeLa cells

    PMID:17172455

    Open questions at the time
    • Structural details of the RAE1–NuMA interface unknown
    • How RAE1 allocation between NuMA and NUP98 is regulated during mitosis unclear
  10. 2010 High

    The 1.65 Å crystal structure of human RAE1–NUP98(GLEBS) revealed a seven-bladed beta-propeller architecture with a conserved basic groove for ssRNA binding, providing the structural framework for understanding both mRNA export and viral mimicry mechanisms.

    Evidence X-ray crystallography at 1.65 Å with mutagenesis validation and RNA-binding assay

    PMID:20498086

    Open questions at the time
    • No structure of RAE1 bound to mRNA substrate
    • How RNA binding contributes to export selectivity unresolved
  11. 2011 High

    A neuronal function was uncovered: Drosophila and C. elegans RAE1 stabilizes the Highwire/RPM-1 E3 ubiquitin ligase by protecting it from autophagy-mediated degradation, with loss of RAE1 causing axon termination and synapse formation defects — extending RAE1 function beyond nucleocytoplasmic transport and mitosis.

    Evidence TAP-MS, co-immunoprecipitation, genetic epistasis, NMJ morphology analysis in Drosophila; MS, co-IP, and epistasis in C. elegans with conservation to human Pam

    PMID:21874015 PMID:22357847

    Open questions at the time
    • Mechanism by which RAE1 shields Highwire from autophagy not defined
    • Whether this function operates in mammalian neurons in vivo unknown
  12. 2012 High

    Transcriptional regulation of murine RAE-1 NKG2D ligands was linked to E2F transcription factors driving expression during cell cycle entry, coupling innate immune surveillance to proliferative status.

    Evidence E2F ChIP at Raet1 promoters, E2F overexpression/knockdown, NKG2D-deficient mouse wound healing model

    PMID:23166357

    Open questions at the time
    • Whether E2F regulation applies to human ULBP orthologs not directly shown
    • Epigenetic layers beyond E2F incompletely mapped
  13. 2014 High

    Crystal structures of VSV M protein bound to RAE1–NUP98 revealed that M protein inserts a methionine finger into the RNA-binding groove of RAE1, directly competing with mRNA — establishing the structural basis for viral hijacking of the export machinery.

    Evidence X-ray crystallography at 3.15 Å, competitive nucleic acid binding assay, synthetic peptide competition

    PMID:24927547

    Open questions at the time
    • Whether all paramyxo/rhabdovirus M proteins use the same mechanism unknown
    • In vivo relevance of groove occupancy vs. other M protein functions not fully separated
  14. 2016 High

    HDAC3 was identified as a transcriptional repressor of RAE-1 NKG2D ligands, with MCMV protein m18 relieving this repression via Casein Kinase II inhibition — defining a viral strategy that paradoxically activates innate immunity.

    Evidence HDAC3 knockout/complementation, m18–CK2 co-immunoprecipitation, ChIP, HDAC inhibitor treatment

    PMID:27874833

    Open questions at the time
    • How HDAC3-mediated repression is maintained in uninfected cells mechanistically incomplete
    • Whether m18-induced RAE-1 has net pro- or anti-viral outcome in vivo unclear
  15. 2021 High

    SARS-CoV-2 ORF6 was shown to bind RAE1–NUP98 via a critical Met58 residue, blocking both mRNA export and protein nuclear import — establishing coronavirus exploitation of the same RAE1 groove targeted by VSV M protein.

    Evidence Co-purification, Met58 mutagenesis, poly(A)+ RNA localization, reporter rescue by RAE1 overexpression, nuclear import assay

    PMID:33849972

    Open questions at the time
    • Structural details not yet available at this point
    • Contribution of RAE1 targeting to COVID-19 pathogenesis unknown
  16. 2022 High

    Crystal structures of SARS-CoV-1 and SARS-CoV-2 ORF6 C-termini bound to RAE1–NUP98 confirmed competitive occupancy of the mRNA-binding groove, unifying the structural mechanism of viral immune evasion across RNA virus families.

    Evidence X-ray crystallography, competitive RNA-binding assay, Met58 mutagenesis

    PMID:35096974

    Open questions at the time
    • Whether therapeutic targeting of the RAE1 groove could block viral evasion untested
    • No structure of RAE1 with a physiological mRNA substrate for comparison

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: the identity and structural basis of physiological mRNA substrates bound in the RAE1 groove during export; how RAE1 is partitioned among its NPC-export, APC/C-inhibitory, NuMA-crosslinking, and chromatin-regulatory functions during the cell cycle; and whether the neuronal Highwire-stabilizing function operates in mammalian neurons in vivo.
  • No structure of RAE1 bound to a physiological mRNA
  • Temporal regulation of RAE1 allocation among distinct complexes undefined
  • Mammalian in vivo validation of neuronal Highwire/Pam stabilization missing

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 6 GO:0098772 molecular function regulator activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0048018 receptor ligand activity 2
Localization
GO:0005634 nucleus 4 GO:0005856 cytoskeleton 3 GO:0005694 chromosome 2 GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-8953854 Metabolism of RNA 7 R-HSA-1640170 Cell Cycle 5 R-HSA-168256 Immune System 5 R-HSA-1643685 Disease 3 R-HSA-9609507 Protein localization 3
Partners
BUB3CDH1KLRK1NUMA1NUP98NXF1RANBP2USP11
Complex memberships
APC/C-Cdh1-RAE1-NUP98Highwire/RPM-1 E3 ligase complexRAE1-NUP98RAE1-NuMA

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 S. pombe Rae1 is required for nuclear export of poly(A)+ RNA; rae1-1 temperature-sensitive mutant accumulates poly(A)+ RNA in the nucleus, and loss of rae1 also causes actin/tubulin disorganization and irreversible G2/M cell cycle arrest. Rae1 encodes a WD40-repeat protein. Temperature-sensitive mutant, fluorescence in situ hybridization (FISH) for poly(A)+ RNA, cell cycle analysis, gene complementation cloning The Journal of biological chemistry High 7706287
1996 S. cerevisiae Gle2 (Rae1 homolog) localizes to nuclear pore complexes, is required for poly(A)+ RNA export (not protein import), and interacts genetically and physically with nucleoporins Nup100p; gle2 mutants show gross NPC and nuclear envelope structural perturbation. Genetic screen (colony-sectoring), indirect immunofluorescence, NPC fractionation, poly(A)+ RNA export assay, two-hybrid interaction Molecular biology of the cell High 8970155
1997 Human RAE1 cDNA partially suppresses the temperature-sensitive mRNA export defect of S. pombe rae1-1 mutant; epitope-tagged human Rae1 localizes to both nucleus and cytoplasm in HeLa cells, consistent with a role in nucleocytoplasmic trafficking. Heterologous complementation in fission yeast, poly(A)+ RNA export assay, immunofluorescence in HeLa cells Gene Medium 9370289
1997 In S. pombe, Rae1 function is required for a process essential for mitotic advancement beyond mRNA export; rae1-deficient cells arrest at G2/M with elevated Cdc2p kinase, lack spindle formation, and lack spindle pole body separation. Rae1p localizes to the nuclear periphery. Temperature-sensitive mutant analysis, immunofluorescence, kinase activity assay, cell cycle arrest characterization Yeast Medium 9301023
1999 Mammalian RAE1 binds directly to a GLEBS-like motif in NUP98 at the nuclear pore complex through multiple domains including WD-repeats and C-terminal extension; RAE1 shuttles between nucleus and cytoplasm in a temperature-dependent, RanGTP-independent manner; overexpression of the GLEBS-like motif inhibits NUP98 binding of RAE1 and causes nuclear accumulation of poly(A)+ RNA, establishing direct RAE1-NUP98 interaction as required for mRNA export. In vitro binding assay, chemical cross-linking, Xenopus oocyte microinjection, overexpression/competition experiments, poly(A)+ RNA localization The Journal of cell biology High 10209021
2000 Ct-RAE1 (Chironomus tentans RAE1 ortholog) does not associate with mRNP cotranscriptionally or in the nucleoplasm but instead binds the exported Balbiani ring RNP particle at the NPC (nuclear pore complex), and this interaction is correlated with presence of an exported RNP in the NPC channel. Immunoelectron microscopy on polytene chromosomes and nuclear pore complexes RNA Medium 11105759
2001 Mouse RAE1 (Rae1beta) is a cell-surface GPI-anchored NKG2D ligand; ectopic expression of Rae1beta on tumor cells causes their rejection by NK cells and/or CD8+ T cells in syngeneic mice, demonstrating RAE1 as a functional NKG2D ligand that triggers anti-tumor immunity. Tumor transfection, in vivo syngeneic rejection assay, NK cell/T cell depletion experiments, immune priming assays Nature High 11557981 11562472
2001 Mouse RAE1 (Rae1gamma, Rae1delta) binds NKG2D with nanomolar affinity; soluble NKG2D-RAE1 interaction requires no additional co-factors. RAE1 and H60 compete directly for NKG2D occupancy, with H60 binding ~25-fold more tightly; the two interactions have distinct thermodynamic profiles (RAE1 interaction less temperature-dependent and makes less use of electrostatics). Surface plasmon resonance, isothermal titration calorimetry, competitive binding assay with soluble recombinant proteins Immunity High 11520456
2001 Human NKG2D forms stable complexes with monomeric MICA and MICB in solution without additional components; it also stably interacts with ULBP/N2DL proteins (human homologs of mouse RAE-1 family); glycosylation of MICA enhances but is not essential for NKG2D binding; a single amino acid at position 129 (alpha2 domain) of MICA alleles controls large differences in NKG2D affinity. Soluble receptor-ligand binding in solution, cell-surface binding assay, allelic variant comparison, mutagenesis Immunogenetics High 11491531
2003 Haploinsufficiency of Rae1 or Bub3 in mice causes mitotic checkpoint defects and chromosome missegregation; Rae1-null mice are embryonic lethal but without detectable mRNA nuclear export defects. Rae1 overexpression corrects both Rae1 and Bub3 haploinsufficiency. Combined Rae1/Bub3 haploinsufficiency greatly increases premature sister chromatid separation and tumorigenesis susceptibility. Conditional knockout mouse generation, chromosome segregation assay, mitotic checkpoint assay, mRNA export assay, overexpression rescue The Journal of cell biology High 12551952
2003 Nup98, Rae1/Gle2, and TAP form specific binary and ternary complexes: Gle2 requires two TAP sites for stable interaction; TAP has highest affinity for a specific GLFG region of Nup98; the ternary Nup98-Gle2-TAP complex can form simultaneously; when Gle2 is Nup98-bound, it no longer binds TAP directly, suggesting Gle2 may deliver TAP to Nup98 during mRNA export. Co-immunoprecipitation, in vitro pulldown binding assays, mapping of interaction domains The Journal of biological chemistry Medium 12637516
2005 VSV matrix (M) protein binds Rae1/mrnp41 directly and blocks mRNA nuclear export; an M protein mutant defective in Rae1 binding cannot inhibit mRNA export; overexpression of Rae1 fully reverts M protein-induced export inhibition; IFN-gamma induces Rae1 expression, providing a host counter-measure. Co-immunoprecipitation, mRNA export assay, M protein mutant analysis, Rae1 overexpression rescue, IFN-gamma induction assay Molecular cell High 15629720
2005 Rae1 is a microtubule-associated protein and spindle assembly factor regulated by the RanGTP/importin-beta pathway in Xenopus egg extracts; Rae1 binds importin beta directly; Rae1 depletion severely inhibits mitotic spindle assembly; a purified Rae1 ribonucleoprotein complex stabilizes microtubules in a RanGTP/importin-beta-regulated manner requiring RNA; RNA itself plays a direct, translation-independent role in spindle assembly. Activity-based purification from Xenopus egg extracts, in vitro spindle assembly assay, immunodepletion, microtubule dynamics assay, RNA requirement test Cell High 15851029
2005 Rae1 and Nup98 form a complex with Cdh1-activated APC (APC-Cdh1) in early mitosis and specifically inhibit APC-Cdh1-mediated ubiquitination of securin (but not cyclin B); combined Rae1/Nup98 haploinsufficiency causes premature securin destruction, premature sister chromatid separation, and severe aneuploidy. Dissociation of Rae1-Nup98 from APC-Cdh1 coincides with BubR1 release from APC-Cdc20 at the metaphase-to-anaphase transition. Mouse haploinsufficiency genetics, co-immunoprecipitation, ubiquitination assay, time-lapse microscopy, securin degradation assay Nature High 16355229
2006 Rae1 and Nup98 form a ternary complex with APC-Cdh1 and securin in prometaphase; the Rae1-Nup98 complex does not prevent APC-Cdh1 from binding securin but instead prevents ubiquitination of already-bound securin, priming rapid securin degradation upon Rae1-Nup98 complex release at metaphase-to-anaphase transition. Co-immunoprecipitation showing ternary complex formation, ubiquitination assay in mouse cells, genetic mouse model Cell cycle High 16479161
2006 Rae1 interacts with NuMA in a mitosis-specific manner; Rae1 binds a specific site on NuMA converting a NuMA dimer into a tetravalent MT crosslinker; reducing Rae1 or increasing NuMA causes multipolar spindle abnormalities; coupling NuMA overexpression to Rae1 overexpression, or NuMA depletion to Rae1 depletion, prevents aberrant spindles; overexpression of the Rae1-binding domain of NuMA alone causes spindle defects. Co-immunoprecipitation (mitosis-specific), domain mapping, RNAi knockdown, overexpression in HeLa cells, spindle phenotype analysis Proceedings of the National Academy of Sciences High 17172455
2010 Crystal structure of human Rae1 in complex with the GLEBS motif of Nup98 at 1.65 Å resolution: Rae1 forms a seven-bladed beta-propeller; Nup98 GLEBS forms an ~50-Å hairpin binding with its C-terminal arm to an invariant hydrophobic surface spanning the top face of the Rae1 beta-propeller; the C-terminal arm of GLEBS is necessary and sufficient for Rae1 binding; a tandem glutamate element is critical for complex formation; the Rae1-Nup98 complex binds single-stranded RNA. X-ray crystallography (1.65 Å), mutagenesis, in vitro binding assay, RNA-binding assay Proceedings of the National Academy of Sciences High 20498086
2011 Drosophila Rae1 is a component of the Highwire (Hiw)/Fsn E3 ubiquitin ligase complex in neurons; Rae1 physically and genetically interacts with Hiw; Rae1 loss causes NMJ morphological defects similar to hiw mutants and deregulates the MAP kinase kinase kinase Wallenda; Rae1 is necessary and sufficient to promote Hiw protein abundance by binding Hiw and protecting it from autophagy-mediated degradation. Tandem affinity purification/mass spectrometry, co-immunoprecipitation, genetic interaction (double mutants), neuromuscular junction morphology assay, Hiw protein stability assay Nature neuroscience High 21874015
2011 RAE1 depletion disrupts NUP98 expression and localization, causing severe chromosome segregation defects; RAE1-NUP98 complex orchestrates proper chromosome segregation; in NUP98-HOXA9-transfected cells and AML patient samples, RAE1 protein is reduced and mislocalized, suggesting RAE1 dysfunction contributes to NUP98 fusion-mediated leukemogenesis. RNAi knockdown, rescue experiments, immunofluorescence, NUP98-HOXA9 transgenic mice, AML patient samples Cell cycle Medium 21467841
2012 C. elegans RAE-1 is an evolutionarily conserved binding partner of RPM-1 (ortholog of human Pam/Highwire); RAE-1 binding region in RPM-1 is conserved and the Rae1-Pam interaction also occurs in humans; RAE-1 loss-of-function causes similar axon termination and synapse formation defects as rpm-1; RAE-1 colocalizes with RPM-1 in neurons and functions downstream of rpm-1. Mass spectrometry, co-immunoprecipitation, genetic epistasis (double mutants), immunofluorescence colocalization The Journal of neuroscience Medium 22357847
2012 VSV M protein forms multiple distinct complexes with Rae1 and Nup98; intermediate molecular weight Rae1-Nup98 complexes interact most efficiently with M protein; silencing Rae1 reduces VSV's ability to inhibit host transcription (but not mRNA nuclear accumulation or translation inhibition); M protein-Rae1-Nup98 complexes associate with the chromatin fraction, suggesting a role in transcription inhibition beyond nuclear transport. Size exclusion chromatography, sedimentation velocity analysis, co-immunoprecipitation, Rae1 siRNA, chromatin fractionation PLoS pathogens Medium 23028327
2014 Crystal structure of the VSV M protein-Rae1-Nup98 ternary complex at 3.15 Å: M protein contacts the Rae1 beta-propeller via two protrusions ('finger' and 'thumb'); conserved Met51 (finger) inserts into a deep hydrophobic pocket on Rae1 with flanking acidic residues bonding to basic groove; M protein competes with oligonucleotide binding to Rae1-Nup98, and the finger peptide alone recapitulates this competition, suggesting Rae1 serves as a phosphate backbone-binding protein for mRNA during export. X-ray crystallography (3.15 Å), competitive nucleic acid binding assay, synthetic peptide competition assay Proceedings of the National Academy of Sciences High 24927547
2016 RAE-1 family NKG2D ligands are transcriptionally repressed by HDAC3 in healthy cells; mouse CMV protein m18 relieves this repression by interacting with Casein Kinase II and preventing it from activating HDAC3, thereby inducing RAE-1 expression; analogously, human herpesvirus HDAC-inhibiting proteins induce the human NKG2D ligand ULBP-1. Genetic knockout/complementation, co-immunoprecipitation (m18-CK2 interaction), HDAC inhibitor treatment, reporter assays, chromatin immunoprecipitation eLife High 27874833
2016 The Hippo pathway targets Rae1 for degradation downstream of Warts/Lats kinase; Rae1 regulates cyclin B levels and organ size; Rae1 loss restricts cyclin B and organ size while Rae1 overexpression increases them; reducing Rae1 suppresses overgrowth caused by Hippo pathway loss; Rae1 acts post-transcriptionally to increase protein levels of Merlin, Hippo, and Warts, creating a feedback circuit. Genetic epistasis (Drosophila), biochemical co-IP, cyclin B quantification, organ size measurement, mammalian cell validation PLoS genetics Medium 27494403
2018 RAE1 is ubiquitinated and the deubiquitinating enzyme USP11 removes ubiquitin from RAE1; USP11 is associated with the mitotic spindle; USP11 knockdown reduces cell proliferation and increases multipolar spindle formation; USP11 functionally modulates RAE1's interaction with NuMA at the mitotic spindle through controlling RAE1 ubiquitination status. Co-immunoprecipitation, ubiquitination assay, lentiviral knockdown, multipolar spindle analysis, spindle immunofluorescence PloS one Medium 29293652
2020 Rae1 acetylation at lysine residues K80 and K87 by acetyltransferases GCN5 and PCAF protects Rae1 (mouse NKG2D ligand) from matrix metalloproteinase-mediated shedding; K80/K87 mutations abolish acetylation and desensitize tumor cells to NKG2D-dependent immune surveillance in vitro and in vivo. In vitro acetylation assay, mutagenesis (K80/K87A), shedding assay, NKG2D-dependent killing assay, in vivo tumor model Cancer letters Medium 33279621
2021 SARS-CoV-2 ORF6 copurifies with Rae1 and Nup98; this interaction is mapped to the C-terminus of ORF6 (Met58 critical); ORF6 causes nuclear entrapment of host mRNA and blocks expression of newly transcribed reporters; Rae1 overexpression restores reporter expression; SARS-CoV-2 ORF6 more strongly copurifies with Rae1/Nup98 than SARS-CoV ORF6; both block nuclear import of a broad range of host proteins through Rae1-Nup98 interactions. Co-purification (affinity), reporter assay, poly(A)+ RNA localization, single amino acid mutagenesis (Met58), Rae1 overexpression rescue, nuclear import assay mBio High 33849972
2022 Crystal structures of SARS-CoV-2 and SARS-CoV-1 ORF6 C-termini in complex with the Rae1-Nup98 heterodimer reveal that ORF6 occupies the same potential mRNA-binding groove of Rae1-Nup98 as VSV M protein; direct tight binding of ORF6 to the Rae1-Nup98 complex competitively inhibits RNA binding; the highly conserved M58 of ORF6 is critical for this interaction. X-ray crystallography, in vitro competitive RNA-binding assay, mutagenesis (M58) Frontiers in molecular biosciences High 35096974
2023 NUP98 and RAE1 are highly expressed in epidermal progenitors forming a nucleoplasmic complex; reduction of NUP98 or RAE1 abolishes regenerative capacity, inhibits proliferation, and induces premature differentiation; NUP98 binds chromatin near transcription start sites of key epigenetic regulators (DNMT1, UHRF1, EZH2) and sustains their expression; HDAC inhibition diminishes NUP98 chromatin binding and causes NUP98 and RAE1 to mislocalize interdependently to the nucleolus. ChIP-seq, knockdown, chromatin fractionation, immunofluorescence, epigenetic regulator expression analysis, HDAC inhibitor treatment Communications biology Medium 37353594
2024 Rae1 is required for SARS-CoV-2 ORF6-mediated inhibition of nucleocytoplasmic transport; Rae1 alone is not necessary to support p-STAT1 import or poly(A) RNA export under basal conditions; loss of Rae1 suppresses the transport inhibitory activity of ORF6; Rae1-Nup98 complex strategically positions ORF6 within the NPC where it alters FG-Nup interactions; Rae1 is required for normal viral protein production during SARS-CoV-2 infection. Rae1 knockdown/knockout, p-STAT1 nuclear import assay, poly(A)+ RNA export assay, viral infection, co-immunoprecipitation Molecular biology of the cell Medium 38507240
2008 Retinoic acid downregulates Rae1 protein and mRNA expression in neuroblastoma cells; Rae1 overexpression prevents retinoic acid-induced APC-Cdh1 activation, Skp2 degradation, p27 accumulation, cell cycle arrest and differentiation; Cdh1 inhibition has similar effects; thus, Rae1 limits APC-Cdh1 activity to promote cell proliferation and its downregulation by retinoic acid facilitates differentiation. Immunoblot, RT-PCR, Rae1 overexpression and knockdown in SH-SY5Y cells, cell cycle analysis, differentiation assay Oncogene Medium 18212744
2012 RAE-1 family NKG2D ligand expression in cancer cell lines and proliferating normal cells is directly coupled to cell cycle entry; E2F transcription factors directly transcriptionally activate Raet1 genes; RAE-1 induction occurs in primary cultures, embryonic brain, and healing wounds; wound healing is delayed in NKG2D-deficient mice. Transcriptional reporter assay, E2F ChIP/binding analysis, E2F overexpression/knockdown, NKG2D-deficient mouse wound healing model The Journal of experimental medicine High 23166357
2014 Induction of RAE1 NKG2D ligands by the DNA damage response requires a STING-dependent DNA sensor pathway involving TBK1 and IRF3; cytosolic DNA detected in RAE1-expressing lymphoma cells required DDR activation; DNA transfection into ligand-negative cells is sufficient to induce RAE1 expression; Irf3-haploinsufficient Eμ-Myc mice show reduced tumor RAE1 levels and reduced survival. STING/TBK1/IRF3 pharmacological inhibition and genetic KO, cytosolic DNA detection, DNA transfection assay, in vivo mouse lymphoma model Cancer research Medium 24590060
2011 RAE-1 expression requires activation of the PI3K pathway (specifically the p110α catalytic subunit) during MCMV infection and transformation; inhibition of p110α blocks RAE-1 induction by MCMV infection and reduces RAE-1 cell surface expression on transformed cells. PI3K isoform-selective pharmacological inhibition, siRNA knockdown of PI3K subunits, cell surface RAE-1 flow cytometry, viral infection assays PLoS pathogens Medium 21966273
2010 MCMV m152/gp40 directly binds RAE-1 isoforms with 1:1 stoichiometry and Kd < 5 μM; binding affinity differs quantitatively among RAE-1 isoforms, corresponding to differential susceptibility to downregulation; RAE-1delta is resistant to downregulation because its mature surface-resident form has an intrinsic property (absence of PLWY motif in beta/gamma does not fully explain delta resistance), suggesting a novel escape mechanism from viral immunoevasion. Protein purification, size exclusion chromatography, analytical ultracentrifugation, isothermal titration calorimetry, cotransfection assay in HEK293T cells Biochemistry High 20166740

Source papers

Stage 0 corpus · 78 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 753 11557981
2001 Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo. Proceedings of the National Academy of Sciences of the United States of America 454 11562472
2001 Interactions of human NKG2D with its ligands MICA, MICB, and homologs of the mouse RAE-1 protein family. Immunogenetics 377 11491531
2003 Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation. The Journal of cell biology 302 12551952
2005 A Rae1-containing ribonucleoprotein complex is required for mitotic spindle assembly. Cell 231 15851029
1999 RAE1 is a shuttling mRNA export factor that binds to a GLEBS-like NUP98 motif at the nuclear pore complex through multiple domains. The Journal of cell biology 206 10209021
2005 VSV disrupts the Rae1/mrnp41 mRNA nuclear export pathway. Molecular cell 197 15629720
2005 The Rae1-Nup98 complex prevents aneuploidy by inhibiting securin degradation. Nature 157 16355229
1996 GLE2, a Saccharomyces cerevisiae homologue of the Schizosaccharomyces pombe export factor RAE1, is required for nuclear pore complex structure and function. Molecular biology of the cell 149 8970155
2006 Early aging-associated phenotypes in Bub3/Rae1 haploinsufficient mice. The Journal of cell biology 148 16476774
2014 RAE1 ligands for the NKG2D receptor are regulated by STING-dependent DNA sensor pathways in lymphoma. Cancer research 145 24590060
1995 A mutation in the Schizosaccharomyces pombe rae1 gene causes defects in poly(A)+ RNA export and in the cytoskeleton. The Journal of biological chemistry 142 7706287
2008 Mononuclear myeloid-derived "suppressor" cells express RAE-1 and activate natural killer cells. Blood 128 18753637
2021 SARS-CoV-2 ORF6 Disrupts Bidirectional Nucleocytoplasmic Transport through Interactions with Rae1 and Nup98. mBio 125 33849972
2018 F-box protein RAE1 regulates the stability of the aluminum-resistance transcription factor STOP1 in Arabidopsis. Proceedings of the National Academy of Sciences of the United States of America 119 30559192
2003 Complex formation among the RNA export proteins Nup98, Rae1/Gle2, and TAP. The Journal of biological chemistry 113 12637516
2007 Retinoic acid signaling sensitizes hepatic stellate cells to NK cell killing via upregulation of NK cell activating ligand RAE1. American journal of physiology. Gastrointestinal and liver physiology 101 17673545
2012 RAE-1 ligands for the NKG2D receptor are regulated by E2F transcription factors, which control cell cycle entry. The Journal of experimental medicine 100 23166357
2010 Structural and functional analysis of the interaction between the nucleoporin Nup98 and the mRNA export factor Rae1. Proceedings of the National Academy of Sciences of the United States of America 99 20498086
2006 Rae1 interaction with NuMA is required for bipolar spindle formation. Proceedings of the National Academy of Sciences of the United States of America 96 17172455
2014 IL-30 (IL27p28) attenuates liver fibrosis through inducing NKG2D-rae1 interaction between NKT and activated hepatic stellate cells in mice. Hepatology (Baltimore, Md.) 89 25351459
1996 Genomic structures and characterization of Rae1 family members encoding GPI-anchored cell surface proteins and expressed predominantly in embryonic mouse brain. Journal of biochemistry 85 8982867
2001 Molecular competition for NKG2D: H60 and RAE1 compete unequally for NKG2D with dominance of H60. Immunity 83 11520456
2012 Complexes of vesicular stomatitis virus matrix protein with host Rae1 and Nup98 involved in inhibition of host transcription. PLoS pathogens 65 23028327
2020 Overexpression of SARS-CoV-2 protein ORF6 dislocates RAE1 and NUP98 from the nuclear pore complex. Biochemical and biophysical research communications 63 33360543
2014 Vesiculoviral matrix (M) protein occupies nucleic acid binding site at nucleoporin pair (Rae1 • Nup98). Proceedings of the National Academy of Sciences of the United States of America 61 24927547
2008 Retinoic acid downregulates Rae1 leading to APC(Cdh1) activation and neuroblastoma SH-SY5Y differentiation. Oncogene 55 18212744
1997 The human RAE1 gene is a functional homologue of Schizosaccharomyces pombe rae1 gene involved in nuclear export of Poly(A)+ RNA. Gene 53 9370289
2006 Securin associates with APCCdh1 in prometaphase but its destruction is delayed by Rae1 and Nup98 until the metaphase/anaphase transition. Cell cycle (Georgetown, Tex.) 51 16479161
2021 Degradation of STOP1 mediated by the F-box proteins RAH1 and RAE1 balances aluminum resistance and plant growth in Arabidopsis thaliana. The Plant journal : for cell and molecular biology 48 33528836
2011 Expression of the RAE-1 family of stimulatory NK-cell ligands requires activation of the PI3K pathway during viral infection and transformation. PLoS pathogens 46 21966273
2003 Natural killer cell-mediated lysis of dorsal root ganglia neurons via RAE1/NKG2D interactions. European journal of immunology 46 12594837
2009 Dual functions of Nicotiana benthamiana Rae1 in interphase and mitosis. The Plant journal : for cell and molecular biology 45 19392703
2011 RNA export factor RAE1 contributes to NUP98-HOXA9-mediated leukemogenesis. Cell cycle (Georgetown, Tex.) 42 21467841
2011 Drosophila Rae1 controls the abundance of the ubiquitin ligase Highwire in post-mitotic neurons. Nature neuroscience 42 21874015
2022 Molecular Mechanism of SARS-CoVs Orf6 Targeting the Rae1-Nup98 Complex to Compete With mRNA Nuclear Export. Frontiers in molecular biosciences 41 35096974
2012 RAE-1, a novel PHR binding protein, is required for axon termination and synapse formation in Caenorhabditis elegans. The Journal of neuroscience : the official journal of the Society for Neuroscience 40 22357847
2009 Differential susceptibility of RAE-1 isoforms to mouse cytomegalovirus. Journal of virology 36 19494006
1997 Advancement through mitosis requires rae1 gene function in fission yeast. Yeast (Chichester, England) 36 9301023
2010 Intact NKG2D-independent function of NK cells chronically stimulated with the NKG2D ligand Rae-1. Journal of immunology (Baltimore, Md. : 1950) 35 20530257
2006 The effect of renal ischemia-reperfusion injury on expression of RAE-1 and H60 in mice kidney. Transplantation proceedings 29 16980040
2013 Drosophila rae1 is required for male meiosis and spermatogenesis. Journal of cell science 26 23788425
2010 Direct interaction of the mouse cytomegalovirus m152/gp40 immunoevasin with RAE-1 isoforms. Biochemistry 26 20166740
2017 Rae1/YacP, a new endoribonuclease involved in ribosome-dependent mRNA decay in Bacillus subtilis. The EMBO journal 25 28363943
2021 Mitotic checkpoint regulator RAE1 promotes tumor growth in colorectal cancer. Cancer science 24 34008277
2011 RAE-1 is expressed in the adult subventricular zone and controls cell proliferation of neurospheres. Glia 23 21046555
2004 Characterization of the Drosophila Rae1 protein as a G1 phase regulator of the cell cycle. Gene 22 14729268
2016 A Herpesviral induction of RAE-1 NKG2D ligand expression occurs through release of HDAC mediated repression. eLife 21 27874833
2018 USP11 deubiquitinates RAE1 and plays a key role in bipolar spindle formation. PloS one 20 29293652
2002 High levels of RAE-1 isoforms on mouse tumor cell lines assessed by anti-"pan" RAE-1 antibody confer tumor susceptibility to NK cells. Biochemical and biophysical research communications 19 11779145
2019 RAE1 mediated ZEB1 expression promotes epithelial-mesenchymal transition in breast cancer. Scientific reports 16 30814639
2000 The Ct-RAE1 protein interacts with Balbiani ring RNP particles at the nuclear pore. RNA (New York, N.Y.) 16 11105759
2024 The RAE1-STOP1-GL2-RHD6 module regulates the ALMT1-dependent aluminum resistance in Arabidopsis. Nature communications 15 39060273
2016 RAE-1 expression is induced during experimental autoimmune encephalomyelitis and is correlated with microglia cell proliferation. Brain, behavior, and immunity 15 27444966
2017 The mitotic checkpoint regulator RAE1 induces aggressive breast cancer cell phenotypes by mediating epithelial-mesenchymal transition. Scientific reports 14 28181567
2016 The Hippo Pathway Targets Rae1 to Regulate Mitosis and Organ Size and to Feed Back to Regulate Upstream Components Merlin, Hippo, and Warts. PLoS genetics 12 27494403
2020 Kupffer Cells Regulate Natural Killer Cells Via the NK group 2, Member D (NKG2D)/Retinoic Acid Early Inducible-1 (RAE-1) Interaction and Cytokines in a Primary Biliary Cholangitis Mouse Model. Medical science monitor : international medical journal of experimental and clinical research 11 32599603
2024 SARS-CoV-2 Orf6 is positioned in the nuclear pore complex by Rae1 to inhibit nucleocytoplasmic transport. Molecular biology of the cell 9 38507240
2023 NUP98 and RAE1 sustain progenitor function through HDAC-dependent chromatin targeting to escape from nucleolar localization. Communications biology 9 37353594
2020 Lysine acetylation of NKG2D ligand Rae-1 stabilizes the protein and sensitizes tumor cells to NKG2D immune surveillance. Cancer letters 9 33279621
2017 Rae1-mediated nuclear export of Rnc1 is an important determinant in controlling MAPK signaling. Current genetics 9 28799069
2017 Activity analysis of LTR12C as an effective regulatory element of the RAE1 gene. Gene 9 28867566
2013 Activation of cellular immunity and marked inhibition of liver cancer in a mouse model following gene therapy and tumor expression of GM-SCF, IL-21, and Rae-1. Molecular cancer 9 24350772
2012 Polymeric delivery of therapeutic RAE-1 plasmid to the pancreatic islets for the prevention of type 1 diabetes. Journal of controlled release : official journal of the Controlled Release Society 9 22910142
2014 Generation of a monoclonal antibody against the glycosylphosphatidylinositol-linked protein Rae-1 using genetically engineered tumor cells. Biological procedures online 8 24495546
2020 Rae1 drives NKG2D binding-dependent tumor development in mice by activating mTOR and STAT3 pathways in tumor cells. Cancer science 7 32333709
2023 Shutdown of multidrug transporter bmrCD mRNA expression mediated by the ribosome-associated endoribonuclease (Rae1) cleavage in a new cryptic ORF. RNA (New York, N.Y.) 5 37142436
2023 RAE1 promotes nitrosamine-induced malignant transformation of human esophageal epithelial cells through PPARα-mediated lipid metabolism. Ecotoxicology and environmental safety 5 37774541
2025 The Chlamydia trachomatis secreted effector CebN targets nucleoporins and Rae1 to antagonize STAT1 nuclear import. bioRxiv : the preprint server for biology 4 38712050
2006 Yisheng injection decreases the expression of H60 and RAE-1 genes in ischemic mice liver. Transplantation proceedings 4 16980045
2024 RAE1 promotes gastric carcinogenesis and epithelial-mesenchymal transition. Archives of biochemistry and biophysics 3 38417691
2017 Saccharomyces cerevisiae Gle2/Rae1 is involved in septin organization, essential for cell cycle progression. Yeast (Chichester, England) 3 28776765
2025 RAE1-armoured DC vaccine boosts NKG2D-CAR-T cells elicited anti-solid tumour treatment. Pharmacological research 2 40683483
2024 Targeting CLK2 and serine/arginine-rich splicing factors inhibits multiple myeloma through downregulating RAE1 by nonsense-mediated mRNA decay mechanism. Cancer science 2 39526400
2025 The RAE1-STOP1 module regulates ABA sensitivity in early seedlings of Arabidopsis. BMC plant biology 0 40360986
2025 Nuclearporin subcomplex Nup98/Rae1 is vital for maternal-to-zygotic transition during early embryonic development. Theriogenology 0 40483744
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