Affinage

NUP42

Nucleoporin NUP42 · UniProt O15504

Length
423 aa
Mass
44.9 kDa
Annotated
2026-06-10
36 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NUP42 (NUPL2) is a cytoplasmic-face FG-nucleoporin that functions as a key positioning and scaffolding factor in directional mRNA export at the nuclear pore complex (PMID:24931410, PMID:28869701). Its carboxy-terminal domain anchors Gle1, binding at an interface distinct from the Gle1-Dbp5/DDX19B site, to assemble a Nup42-CTD/Gle1/Dbp5 complex that, together with IP6, stimulates the RNA-dependent ATPase activity of the DEAD-box protein Dbp5/DDX19B for mRNP remodeling; loss of NUP42 abolishes the Gle1-Dbp5 interaction, and this activation mechanism is conserved from yeast to human (PMID:16783363, PMID:28869701). Crystal structures of Gle1•Nup42•DDX19 capture the rearrangement of DDX19 from an auto-inhibited to an RNA-binding-competent state, with human DDX19 activation being IP6-independent (PMID:29899397). In parallel, the FG repeats of Nup42 (with those of Nup159) position mRNPs for Gle1/Dbp5 remodeling, since fusing the Nup42 FG domain to Gle1 bypasses the requirement for endogenous Nup42 FG (PMID:24931410). NUP42 also serves as an accessory factor for CRM1-dependent protein export: human NUPL2 binds CRM1 and the HIV-1 Rev NES, promotes formation of CRM1•RanGTP complexes independently of its FG repeats, and acts as a reaction intermediate that is displaced by RanBP1 and Nup214 (PMID:10358091, PMID:10347184, PMID:22250199). Beyond export, NUP42 contributes to stress responses, suppressing heat-induced nuclear condensation of chaperone mRNAs to sustain chaperone production and thermotolerance (PMID:41727045), and its fission yeast ortholog Amo1 bridges the RIXC complex and the FACT histone chaperone at the nuclear periphery to suppress histone turnover and maintain heterochromatin (PMID:31883795).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1999 Medium

    Established the first molecular partners of human NUPL2, placing it on the CRM1-dependent protein export pathway through interaction with the HIV-1 Rev NES and CRM1.

    Evidence Yeast two-hybrid and WGA chromatography for O-glycosylation in human cells

    PMID:10358091

    Open questions at the time
    • No reciprocal Co-IP or in-cell functional consequence demonstrated
    • Role of the zinc finger and coiled-coil domains undefined
  2. 1999 Medium

    Reconstituted the sequential biochemistry showing Nup42 acts as a Crm1/RanGTP reaction intermediate that releases export cargo and is in turn displaced by RanBP1, defining its mechanistic position in nuclear export.

    Evidence In vitro binding assays with recombinant Rev/Crm1/RanGTP and Nup proteins

    PMID:10347184

    Open questions at the time
    • In vitro reconstitution only, no cellular validation
    • Relative contribution of Nup42 versus Nup159 unresolved
  3. 1999 Medium

    Linked yeast Nup42 to the SUMO protease Ulp1 at the NPC, hinting at a connection between Nup42-anchored complexes and SUMO regulation.

    Evidence Yeast two-hybrid screening and co-immunoprecipitation in S. cerevisiae

    PMID:11056382

    Open questions at the time
    • Functional significance of the Ulp1 association not established
    • No follow-up connecting SUMO processing to Nup42 export function
  4. 2004 Medium

    Genetically placed Nup42 at the cytoplasmic face in the Gle1-IP6 mRNA export pathway and showed its FG repeats are dispensable for this genetic function, separating positioning from anchoring roles.

    Evidence Synthetic lethality and FG-domain complementation analysis in S. cerevisiae

    PMID:15459192

    Open questions at the time
    • Did not define the biochemical step Nup42 contributes to
    • Direct Gle1 anchoring role not yet structurally resolved
  5. 2006 High

    Demonstrated that Gle1, anchored via Nup42, together with IP6 stimulates Dbp5 ATPase activity, establishing the biochemical output of the Nup42/Gle1 module in mRNA export.

    Evidence In vitro ATPase kinetics with recombinant proteins and DBP5 genetic suppression of ipk1 nup42 mutants in S. cerevisiae

    PMID:16783363

    Open questions at the time
    • Direct Nup42-Gle1 interaction interface not yet defined
    • Did not establish how Nup42 contributes structurally to activation
  6. 2010 Medium

    Connected Nup42 to stress-responsive mRNA retention, showing its function intersects the Slt2 MAP kinase pathway controlling thermotolerance.

    Evidence Genetic double-mutant (nup42 nab2) thermotolerance assay in S. cerevisiae

    PMID:20823268

    Open questions at the time
    • Mechanism of Nup42 in mRNA retention not resolved
    • Direct molecular link to Slt2 signaling not shown
  7. 2012 High

    Provided cellular gain- and loss-of-function evidence that human NUPL2 promotes CRM1-dependent export and forms RanBP1/Nup214-dissociable CRM1•RanGTP complexes independently of its FG repeats.

    Evidence Fluorescence localization, reciprocal Co-IP, siRNA knockdown, and overexpression export assays in mammalian cells

    PMID:22250199

    Open questions at the time
    • How NUPL2 stabilizes CRM1•RanGTP mechanistically unresolved
    • Relationship between protein-export and mRNA-export functions not integrated
  8. 2014 High

    Resolved the role of the Nup42 FG domain, showing it positions mRNPs for Gle1/Dbp5 remodeling at the cytoplasmic face, separable from Gle1 anchoring.

    Evidence Genetic FG-domain deletion/swap, RNA cross-linking, and synthetic lethality with dbp5/gle1 in S. cerevisiae

    PMID:24931410

    Open questions at the time
    • Structural basis of FG-mRNP positioning not defined
    • FG-domain specificity determinants only partially mapped
  9. 2017 High

    Defined the Nup42 CTD as the Gle1 anchor and showed a Nup42-CTD/Gle1/Dbp5 trimeric complex with IP6 activates the ATPase, with the mechanism conserved between yeast and human.

    Evidence Domain deletion/point mutants, Co-IP, in vitro ATPase reconstitution, and mRNA export assays in yeast and human cells

    PMID:28869701

    Open questions at the time
    • Atomic structure of the trimeric complex not yet provided in this study
    • How CTD binding alters Gle1 activity not structurally explained
  10. 2018 High

    Provided atomic-resolution mechanism, capturing the Gle1•Nup42•DDX19 rearrangement of DDX19 to an RNA-competent state and showing human DDX19 activation is IP6-independent and tied to Gle1 thermostability.

    Evidence Multiple X-ray crystal structures with ATPase reconstitution, thermal stability assays, and disease-mutation analysis

    PMID:29899397

    Open questions at the time
    • In vivo dynamics of the remodeling cycle at the NPC not captured
    • How disease-linked Gle1 destabilization perturbs export in cells not directly shown
  11. 2019 High

    Revealed a distinct chromatin function for the fission yeast ortholog Amo1, bridging the RIXC complex and FACT at the nuclear periphery to suppress histone turnover and maintain heterochromatin.

    Evidence Genetic screen, Co-IP/co-purification, ChIP, epistasis, and histone-turnover readouts in S. pombe

    PMID:31883795

    Open questions at the time
    • Whether human NUPL2 has an analogous chromatin-silencing role unknown
    • Connection between heterochromatin function and export function unestablished
  12. 2022 Medium

    Linked proper cytoplasmic-face localization of Nup42 to Brl1-mediated nuclear membrane fusion during NPC assembly.

    Evidence Fluorescence microscopy of Nup42 localization in brl1 mutants with AlphaFold-guided mutagenesis in S. cerevisiae

    PMID:35293775

    Open questions at the time
    • Nup42 mislocalization is a secondary observation in a Brl1 study
    • Direct assembly determinants for Nup42 not mapped
  13. 2024 Medium

    Showed NUP42 is a target of viral subversion, undergoing dispersion and a mobility shift during coronavirus infection that contributes to disruption of nucleocytoplasmic trafficking.

    Evidence Immunofluorescence, SDS-PAGE mobility shift, interactome, and siRNA in an IBV infection model

    PMID:39602452

    Open questions at the time
    • The specific modification driving the NUP42 mobility shift is not resolved
    • Direct contribution of NUP42 dispersal to immune suppression not isolated from other FG-Nups
  14. 2026 Medium

    Identified Nup42 as the strongest suppressor of heat-induced mRNA condensation, connecting its export function to maintenance of translatable chaperone mRNAs and thermotolerance.

    Evidence Genome-wide CRISPRi screen (FRep-Seq), mRNA fractionation, translation, and thermosensitivity assays (preprint)

    PMID:41727045

    Open questions at the time
    • Not yet peer-reviewed
    • How co-transcriptional mRNP packaging is mechanistically coupled to Nup42 unresolved
    • Direct molecular determinant of condensation suppression unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NUP42's roles in mRNA export, CRM1-dependent protein export, stress-induced mRNA condensation, and peripheral chromatin maintenance are coordinated within a single protein at the pore remains unresolved.
  • No unified structural/functional model linking the export and chromatin functions
  • Whether the human protein recapitulates the ortholog's chromatin role untested
  • In vivo dynamics of the Gle1/Dbp5 remodeling cycle at the pore not captured

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2 GO:0005198 structural molecule activity 1
Localization
GO:0005634 nucleus 1 GO:0005635 nuclear envelope 1
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-9609507 Protein localization 2 R-HSA-4839726 Chromatin organization 1
Partners
CRM1DBP5DDX19BGLE1NUP159NUP214ULP1
Complex memberships
Nup42-CTD/Gle1/Dbp5 (DDX19) complexnuclear pore complex (cytoplasmic face)

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Gle1 (anchored to the NPC via Nup42) and inositol hexakisphosphate (InsP6) together stimulate the RNA-dependent ATPase activity of the DEAD-box protein Dbp5 during mRNA export; InsP6 alone had minimal effect and required both Dbp5 and Gle1 for maximal binding. Overexpression of DBP5 suppressed mRNA export and growth defects of an ipk1 nup42 double mutant, placing Nup42 in the same pathway. In vitro ATPase kinetic assays with recombinant proteins; genetic suppression analysis (DBP5 overexpression in ipk1 nup42 mutant); genetic epistasis in S. cerevisiae Nature cell biology High 16783363
1999 Human NLP1/NUPL2 (nucleoporin-like protein 1) interacts with the HIV-1 Rev nuclear export signal and with CRM1, both in yeast two-hybrid and mammalian cell assays. The protein contains FG repeats, high serine content, a putative zinc finger, and a coiled-coil domain, and is O-glycosylated. Yeast two-hybrid screening; wheat germ agglutinin chromatography for O-glycosylation; gene expression analysis The Journal of biological chemistry Medium 10358091
1999 Yeast Nup42 was identified as an Ulp1-interacting protein by two-hybrid screening, and Gle1 (another NPC component that interacts with Nup42) also co-immunoprecipitated with Ulp1, placing Nup42 at the NPC in association with the SUMO protease Ulp1. Yeast two-hybrid screening; co-immunoprecipitation Journal of biochemistry Medium 11056382
1999 Yeast Nup42 (and Nup159) form a Nup/Crm1/RanGTP complex after reaction with a Rev/Crm1/RanGTP complex, concomitantly releasing Rev; RanBP1 can then displace the Nup, demonstrating that Nup42 is a reaction intermediate in Crm1-mediated nuclear export. In vitro binding assay with recombinant proteins; identification of putative reaction intermediates The Journal of biological chemistry Medium 10347184
2004 Genetic analysis in S. cerevisiae showed that nup42Δ ipk1Δ double mutants are synthetically lethal/sick, and complementation did not require the FG repeat domain of Nup42, indicating that IP6 produced by Ipk1 acts at a step after heterogeneous nuclear ribonucleoprotein targeting to the NPC and that Nup42 functions at the cytoplasmic face in the Gle1-IP6 mRNA export pathway. Synthetic lethality/fitness analysis; complementation with FG-domain deletion constructs; spatial restriction of Ipk1 using membrane anchors The Journal of biological chemistry Medium 15459192
2010 In S. cerevisiae heat shock, Nup42 participates in thermotolerance: a nup42 nab2-T178A/S180A double mutant has decreased thermotolerance, linking Nup42 function to the MAP kinase Slt2-dependent mRNA retention pathway under stress. Genetic double-mutant analysis; thermotolerance assay Molecular and cellular biology Medium 20823268
2012 Human NLP1/NUPL2 localizes to the nuclear envelope and is mobile within the nucleus; it promotes formation of CRM1•RanGTP complexes (with or without NES cargo), which can be dissociated by RanBP1 and Nup214. The FG repeats of NLP1 are not required for CRM1 binding. Overexpression of NLP1 promotes CRM1-dependent export, and siRNA-mediated depletion reduces export rates. Fluorescence microscopy (localization); co-immunoprecipitation; siRNA knockdown with nuclear export assay; overexpression assay Journal of cell science High 22250199
2014 The FG repeat domains of both Nup42 and Nup159 at the cytoplasmic face of the NPC are required for efficient mRNP remodeling during export; deletion of both FG domains causes a cold-sensitive poly(A)+ mRNA export defect and synthetic lethality with dbp5 and gle1 mutants. FG domain swaps showed that only certain FG domains are functional at the cytoplasmic face, and fusing the Nup42 FG domain to Gle1 bypasses the need for endogenous Nup42 FG, demonstrating its role in positioning mRNPs for Gle1/Dbp5 remodeling. Genetic deletion and FG-domain swap analysis; poly(A)+ mRNA export assay; RNA cross-linking; synthetic lethality with dbp5/gle1 mutants Genetics High 24931410
2017 The Nup42 carboxy-terminal domain (CTD) binds Gle1/hGle1B at an interface distinct from the Gle1-Dbp5/hDDX19B interaction site; a Nup42-CTD/Gle1-CTD/Dbp5 trimeric complex forms in the presence of IP6. Deletion of NUP42 abrogates the Gle1-Dbp5 interaction. In vitro, Nup42-CTD and IP6 stimulate Gle1/hGle1B activation of Dbp5 and DDX19B in similar, non-additive manners. This mechanism is fully conserved between yeast and human cells. Structure-function analysis with domain deletions/point mutants; co-immunoprecipitation; in vitro ATPase reconstitution; mRNA export assays in S. cerevisiae and human cells Traffic (Copenhagen, Denmark) High 28869701
2018 Crystal structures of Gle1•Nup42 from three organisms reveal a conserved binding mode; crystal structures of human Gle1•Nup42•DDX19 capture the structural rearrangement in DDX19 from an auto-inhibited to an RNA-binding competent state. Biochemical reconstitution showed that human DDX19 activation does not require IP6 (unlike fungal homologs), and that Gle1 thermostability affects DDX19 activation. Disease-linked mutations reduce Gle1 thermostability. X-ray crystallography (Gle1•Nup42 and Gle1•Nup42•DDX19); in vitro ATPase reconstitution; thermal stability assays; mutation analysis Nature communications High 29899397
2019 In fission yeast, the Nup42 ortholog Amo1 (NUPL2) is required at the nuclear periphery for propagation of heterochromatin. Amo1 associates with the Rix1-containing RNA processing complex (RIXC) and the histone chaperone complex FACT. RIXC connects heterochromatin protein Swi6HP1 to Amo1 at the nuclear rim; Amo1 in turn enables Swi6 association with FACT, which precludes histone turnover, thereby promoting gene silencing and epigenetic stability. Genetic screen; co-immunoprecipitation/co-purification; ChIP; epistasis analysis; deletion mutants with silencing and histone turnover readouts Cell High 31883795
2022 Mislocalization of Nup42 (along with Nup159) to petal-like structures occurs when yeast Brl1 AαH (amphipathic α-helix) function is compromised, linking Brl1-mediated INM/ONM fusion during NPC assembly to proper cytoplasmic-face localization of Nup42. Fluorescence microscopy of Nup localization in brl1 mutants; AlphaFold structural prediction followed by mutagenesis Molecular biology of the cell Medium 35293775
2024 During coronavirus (IBV) infection, NUP42 (along with other FG-Nups) undergoes cytosolic dispersion from the nuclear envelope and exhibits a size mobility shift. The IBV nucleocapsid N protein, by recruiting p-PKCα to RACK1, drives phosphorylation and cytoplasmic redistribution of NUP62 and dispersal of FG-Nups including NUP42, thereby disrupting nucleocytoplasmic trafficking and suppressing innate immune gene expression. Immunofluorescence microscopy; SDS-PAGE mobility shift; interactome/co-immunoprecipitation; siRNA knockdown; viral infection model PLoS pathogens Medium 39602452
2026 Nup42 suppresses heat-induced mRNA condensation: loss of Nup42 triggers nuclear condensation of chaperone mRNAs that are exported but remain translationally incompetent, impairing chaperone production and causing thermosensitivity. A genome-wide CRISPRi screen identified Nup42 as the strongest suppressor of heat-induced mRNA condensation, and co-transcriptional mRNP packaging was found to be a critical determinant of condensation in Nup42-deficient cells. Genome-wide CRISPRi screen (FRep-Seq); mRNA fractionation; translation assays; thermosensitivity assays bioRxivpreprint Medium 41727045

Source papers

Stage 0 corpus · 36 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Inositol hexakisphosphate and Gle1 activate the DEAD-box protein Dbp5 for nuclear mRNA export. Nature cell biology 239 16783363
2010 Neuropeptide feedback modifies odor-evoked dynamics in Caenorhabditis elegans olfactory neurons. Nature neuroscience 190 20364145
2021 Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets. JAMA neurology 155 33523105
1999 Neuropeptide gene families in the nematode Caenorhabditis elegans. Annals of the New York Academy of Sciences 142 10676452
2019 Positioning Heterochromatin at the Nuclear Periphery Suppresses Histone Turnover to Promote Epigenetic Inheritance. Cell 96 31883795
2017 Artificial intelligence in neurodegenerative disease research: use of IBM Watson to identify additional RNA-binding proteins altered in amyotrophic lateral sclerosis. Acta neuropathologica 92 29134320
2000 Yeast Ulp1, an Smt3-specific protease, associates with nucleoporins. Journal of biochemistry 70 11056382
2017 Increased brain expression of GPNMB is associated with genome wide significant risk for Parkinson's disease on chromosome 7p15.3. Neurogenetics 61 28391543
1982 Yeast killer plasmid mutations affecting toxin secretion and activity and toxin immunity function. Molecular and cellular biology 59 7050670
2018 Structural and functional analysis of mRNA export regulation by the nuclear pore complex. Nature communications 58 29899397
2010 The mitogen-activated protein kinase Slt2 regulates nuclear retention of non-heat shock mRNAs during heat shock-induced stress. Molecular and cellular biology 56 20823268
2013 MRNA and miRNA expression patterns associated to pathways linked to metal mixture health effects. Gene 55 24080485
1999 Putative reaction intermediates in Crm1-mediated nuclear protein export. The Journal of biological chemistry 53 10347184
2014 Dissecting the signaling mechanisms underlying recognition and preference of food odors. The Journal of neuroscience : the official journal of the Society for Neuroscience 45 25009271
2004 Cytoplasmic inositol hexakisphosphate production is sufficient for mediating the Gle1-mRNA export pathway. The Journal of biological chemistry 45 15459192
2017 Nup42 and IP6 coordinate Gle1 stimulation of Dbp5/DDX19B for mRNA export in yeast and human cells. Traffic (Copenhagen, Denmark) 40 28869701
1999 A new nucleoporin-like protein interacts with both HIV-1 Rev nuclear export signal and CRM-1. The Journal of biological chemistry 34 10358091
2015 A genome-wide association study of chronic obstructive pulmonary disease in Hispanics. Annals of the American Thoracic Society 32 25584925
2014 Nucleoporin FG domains facilitate mRNP remodeling at the cytoplasmic face of the nuclear pore complex. Genetics 29 24931410
2016 Dead Lactobacillus plantarum Stimulates and Skews Immune Responses toward T helper 1 and 17 Polarizations in RAW 264.7 Cells and Mouse Splenocytes. Journal of microbiology and biotechnology 24 26699750
2012 The nucleoporin-like protein NLP1 (hCG1) promotes CRM1-dependent nuclear protein export. Journal of cell science 23 22250199
1989 NLP-1: a DNA intercalating hypoxic cell radiosensitizer and cytotoxin. International journal of radiation oncology, biology, physics 23 2703383
1991 Targeting radiosensitizers to DNA by attachment of an intercalating group: nitroimidazole-linked phenanthridines. Radiation research 20 2068275
2022 Mendelian Randomization Study Using Dopaminergic Neuron-Specific eQTL Nominates Potential Causal Genes for Parkinson's Disease. Movement disorders : official journal of the Movement Disorder Society 17 36177513
2019 Identification of key HIF-1α target genes that regulate adaptation to hypoxic conditions in Tibetan chicken embryos. Gene 14 31887331
2022 A perinuclear α-helix with amphipathic features in Brl1 promotes NPC assembly. Molecular biology of the cell 12 35293775
2013 Microarray profiling of mononuclear peripheral blood cells identifies novel candidate genes related to chemoradiation response in rectal cancer. PloS one 11 24040155
1992 Mechanistic studies of enhanced in vitro radiosensitization and hypoxic cell cytotoxicity by targeting radiosensitizers to DNA via intercalation. International journal of radiation oncology, biology, physics 9 1735693
2024 Coronavirus nucleocapsid protein enhances the binding of p-PKCα to RACK1: Implications for inhibition of nucleocytoplasmic trafficking and suppression of the innate immune response. PLoS pathogens 7 39602452
2024 Global analysis of neuropeptide receptor conservation across phylum Nematoda. BMC biology 6 39379997
2024 Neuronal PRDX-2-Mediated ROS Signaling Regulates Food Digestion via peripheral UPRmt Activation. Nature communications 5 39632952
2023 Early pheromone perception remodels neurodevelopment and accelerates neurodegeneration in adult C. elegans. Cell reports 3 37289584
2026 Nup42 safeguards heat-induced mRNAs from nuclear condensation to support chaperone synthesis. bioRxiv : the preprint server for biology 0 41727045
2026 Mitochondrial calcium modulates odor-mediated behavioral plasticity in Caenorhabditis elegans. Molecules and cells 0 42092527
2025 The visual outcome and efficacy of current therapies for neurosarcoidosis with anterior visual pathway involvement: A systemic review. Journal of neuroimmunology 0 41043325
2025 IDENTIFICATION of NLP-5 and NLP-6 as potential ligands for the NPR-9 receptor in Caenorhabditis elegans. General and comparative endocrinology 0 41360305

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