{"gene":"NUP35","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2006,"finding":"The crystal structure of the RRM domain of mouse Nup35 was solved at 2.7 Å resolution, revealing an atypical betaalphabetabetaalphabeta topology with non-canonical RNP1 and RNP2 motifs. The RRM domain forms a homodimer both in crystal and in solution (analytical ultracentrifugation), with homodimerization driven primarily by hydrophobic interactions involving Met236 (beta4), Phe178 (beta1), and Trp209 (beta3).","method":"X-ray crystallography (2.7 Å) + analytical ultracentrifugation","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with orthogonal solution-phase validation by analytical ultracentrifugation","pmids":["16962612"],"is_preprint":false},{"year":2006,"finding":"NUP35 (Nup53) was identified as a component of the mammalian nuclear pore complex proteome, establishing its identity as a nucleoporin.","method":"Biochemical purification of NPC fraction + mass spectrometry","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — proteomic identification from purified NPC fraction, widely replicated","pmids":["12196509"],"is_preprint":false},{"year":2006,"finding":"NDC1, a transmembrane nucleoporin, directly interacts with Nup53 (NUP35) in vitro, linking the NE membrane to soluble nucleoporins during NPC assembly. RNAi of NDC1 phenocopies depletion of Nup93, Nup53, and Nup205, placing NDC1 and Nup53 in the same functional pathway for NPC assembly.","method":"In vitro binding assay + RNAi epistasis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — direct in vitro interaction combined with genetic epistasis by RNAi","pmids":["16600873"],"is_preprint":false},{"year":2008,"finding":"In vivo loss-of-function of Nup35/NPP-19 in C. elegans (npp-19(tm2886) mutant) causes chromosome missegregation, nuclear morphology defects, and embryonic lethality. Depletion of Nup35/NPP-19 specifically blocks NE localization of Nup155/NPP-8, NPC assembly, and nuclear lamina formation, while nuclear membrane targeting and Nup107/NPP-5 recruitment to chromatin remain Nup35-independent, indicating Nup35 acts downstream of membrane recruitment but upstream of NPC scaffold assembly.","method":"C. elegans genetic loss-of-function (temperature-sensitive allele) + immunofluorescence localization of NPC components","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic loss-of-function with specific phenotypic readouts and epistasis for multiple NPC components","pmids":["19146848"],"is_preprint":false},{"year":2011,"finding":"Nup35 is required for the Ran-dependent mechanism of integral membrane protein translocation to the inner nuclear membrane. FG repeats added to membrane proteins reduce FRAP recovery times, and this effect also depends on Nup35, suggesting that Nup35 facilitates FG-mediated transport through the peripheral channels of the NPC.","method":"FRAP with ATP/Ran depletion conditions + siRNA knockdown of Nup35","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — FRAP with multiple perturbation conditions (ATP depletion, Ran depletion, Nup35 siRNA) and modeling across 15 proteins","pmids":["21444689"],"is_preprint":false},{"year":2011,"finding":"FG repeats on integral membrane proteins facilitate their own transport to the inner nuclear membrane via a mechanism requiring Nup35, which itself contains FG repeats, suggesting these proteins use FG-FG interactions to act as their own nuclear transport receptors through NPC peripheral channels.","method":"FG-repeat addition to membrane proteins + FRAP + Nup35 requirement demonstrated by knockdown","journal":"Communicative & integrative biology","confidence":"Medium","confidence_rationale":"Tier 3 — mechanistic interpretation supported by FRAP data, but commentary/follow-up paper based on primary FRAP study","pmids":["22046461"],"is_preprint":false},{"year":2013,"finding":"Nup53 (NUP35 vertebrate ortholog in Xenopus/vertebrate context) interacts with Ndc1 and Nup155. The Ndc1-binding site on Nup53 overlaps with its membrane-bending region, and this interaction modulates membrane-deforming activity. Nup53-Nup155 interaction is the main determinant for recruiting Nup155 to the assembling NPC. Disruption of either interaction blocks vertebrate NPC assembly.","method":"Co-immunoprecipitation, in vitro binding assays, RNAi depletion with NPC assembly phenotype readout","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (biochemical binding, RNAi, functional NPC assembly assay) in single study","pmids":["24363447"],"is_preprint":false},{"year":2015,"finding":"NUP35 regulates cardiomyocyte pH homeostasis by controlling nucleo-cytoplasmic trafficking of NHE1 (nhe1) mRNA. The N-terminal domain of NUP35 mediates nhe1 mRNA nuclear export by targeting the 5'-UTR (-412 to -213 nt) of nhe1 mRNA. NUP35 ablation reduces NHE1 expression and weakens resistance to acid challenge. NUP35 and NHE1 are co-downregulated in ischemic cardiomyocytes, and enforced NUP35 expression counteracts anoxia-induced acidification.","method":"siRNA knockdown, overexpression, mRNA export assay, in vivo/in vitro ischemia model","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple functional assays but mechanism of RNA targeting is based on domain deletion rather than direct binding reconstitution","pmids":["26260029"],"is_preprint":false},{"year":2016,"finding":"A point mutation in the RNA recognition motif of Nup35 in mice causes a degenerative myopathy specifically affecting colonic smooth muscle, leading to megacolon and reduced lifespan, demonstrating that Nup35 RRM domain function is required for smooth muscle integrity in vivo.","method":"ENU point mutation in mouse Nup35 RRM domain; histopathological analysis","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo genetic model with specific tissue phenotype, but molecular mechanism not fully resolved","pmids":["27427419"],"is_preprint":false},{"year":2016,"finding":"The stoichiometry of Nup35 within the human NPC was experimentally estimated at approximately 23 copies per nuclear pore complex using a GFP single-molecule fluorescence standard with endogenous knockdown and GFP-knockdown-resistant replacement.","method":"Quantitative single-molecule fluorescence microscopy with spinning disk confocal + knockdown/replacement approach","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — direct quantitative measurement with appropriate controls for copy number determination","pmids":["27613095"],"is_preprint":false},{"year":2018,"finding":"Nup35 dynamically relocalizes during oocyte meiosis: it resides at the nuclear membrane at the germinal vesicle (GV) stage, then redistributes to microtubules and the spindle during pro-MI, MI, and MII, and to spindle poles at AI and TI. Nup35 appears in a phosphorylated form after meiotic resumption (GVBD). siRNA knockdown of Nup35 impairs first polar body extrusion, spindle assembly, chromosome alignment, and kinetochore-microtubule attachment, and activates the spindle assembly checkpoint. Knockdown also dissociates p-ERK1/2 from spindle poles.","method":"Immunofluorescence localization, siRNA knockdown, spindle assembly checkpoint activation assay, phosphorylation detection by Western blot","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct localization with functional consequence, siRNA KD with multiple specific phenotypic readouts, but single lab study","pmids":["30195030"],"is_preprint":false},{"year":2022,"finding":"Rapid auxin-mediated depletion of NUP35 in human cells demonstrates that NUP35, unlike NUP93, does not directly control gene transcription. NUP35 depletion causes no significant changes in gene expression, 3D genome organization (A/B compartments, TADs), or enhancer-promoter contacts as measured by Hi-C and HiChIP.","method":"Auxin-inducible degron rapid depletion + Cut&Run + Hi-C + HiChIP","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 — rapid depletion with multiple orthogonal genome-wide assays, rigorous controls","pmids":["36323253"],"is_preprint":false},{"year":2023,"finding":"Nup35 makes direct physical interactions with HIV-1 capsid (CA) via regions containing FG motifs, supporting HIV-1 nuclear entry. This interaction is dependent on cyclophilin A (CypA) interaction with CA. Knockdown of Nup35 reduces HIV-1 nuclear entry efficiency, placing Nup35 among NPC components that the HIV-1 capsid core exploits as a macromolecular nuclear transport receptor.","method":"siRNA knockdown of Nup35 + direct binding assay of FG motifs with HIV-1 CA + CypA mutant analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding demonstrated with FG motif regions, functional KD phenotype in viral nuclear entry","pmids":["37355754"],"is_preprint":false},{"year":2025,"finding":"Cardiac-specific Nup35 knockout mice develop severe cardiac fibrosis, hypertrophy, and dysfunction; Nup35 overexpression is protective. Mechanistically, Nup35 directly binds Wif1 mRNA (shown by RNA immunoprecipitation sequencing), retaining pre-mRNA of Wif1 in the nucleus and decreasing Wif1 protein in Nup35-deficient cardiomyocytes. AAV9-mediated Wif1 restoration rescues the cardiac phenotype of Nup35 knockout mice, placing Nup35 upstream of Wif1 in the WNT pathway during pathological cardiac remodeling.","method":"Cardiac-specific knockout/overexpression mouse models + RNA immunoprecipitation sequencing (RIP-seq) + AAV9 rescue","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 1–2 — in vivo genetic KO/OE with specific phenotype, direct RNA binding shown by RIP-seq, epistasis established by AAV rescue","pmids":["41145234"],"is_preprint":false}],"current_model":"NUP35 is a nucleoporin of the NPC inner ring whose RRM domain forms homodimers and binds mRNA; it physically interacts with Ndc1, Nup155, and Nup93 to scaffold NPC assembly and anchor the pore membrane, facilitates Ran-dependent FG-mediated translocation of integral proteins to the inner nuclear membrane, selectively controls nuclear export of specific mRNAs (including NHE1 and Wif1) to regulate cardiomyocyte pH homeostasis and WNT signaling in cardiac remodeling, localizes to the meiotic spindle where it supports spindle assembly and chromosome segregation, and provides FG-motif-dependent docking sites for HIV-1 capsid during nuclear entry."},"narrative":{"teleology":[{"year":2002,"claim":"Establishing NUP35 as a bona fide component of the mammalian NPC resolved its identity as a nucleoporin and placed it within the pore proteome for subsequent mechanistic dissection.","evidence":"Biochemical purification of NPC fraction coupled with mass spectrometry","pmids":["12196509"],"confidence":"High","gaps":["Position within the NPC substructure was not defined","No interaction partners identified at this stage"]},{"year":2006,"claim":"Solving the crystal structure of the NUP35 RRM domain revealed an atypical RNA-recognition fold that homodimerizes through specific hydrophobic contacts, providing the first structural framework for understanding its dual roles in self-assembly and RNA binding.","evidence":"X-ray crystallography at 2.7 Å of mouse Nup35 RRM domain with analytical ultracentrifugation","pmids":["16962612"],"confidence":"High","gaps":["RNA substrates recognized by the RRM domain were not identified","Functional consequences of homodimerization in NPC context were untested"]},{"year":2006,"claim":"Demonstrating that the transmembrane nucleoporin Ndc1 directly binds NUP35 in vitro and that RNAi of either protein produces equivalent NPC assembly defects established the Ndc1–NUP35 axis as a membrane-to-scaffold bridge during pore biogenesis.","evidence":"In vitro binding assay and RNAi epistasis in mammalian cells","pmids":["16600873"],"confidence":"High","gaps":["Structural basis of the Ndc1–NUP35 interface was unknown","Whether Ndc1 binding modulates NUP35 membrane deformation was untested"]},{"year":2008,"claim":"Genetic loss-of-function in C. elegans placed NUP35 downstream of nuclear membrane recruitment but upstream of Nup155 and full NPC scaffold assembly, defining its hierarchical position in pore biogenesis.","evidence":"C. elegans npp-19 temperature-sensitive mutant with immunofluorescence of NPC component localization","pmids":["19146848"],"confidence":"High","gaps":["Whether this hierarchy is conserved in vertebrate post-mitotic NPC assembly was not confirmed","Molecular basis for NUP35-dependent Nup155 recruitment was undefined"]},{"year":2011,"claim":"NUP35 was shown to be required for Ran-dependent translocation of integral membrane proteins to the inner nuclear membrane via FG-repeat interactions, extending its function beyond scaffold assembly to active gating of peripheral NPC channels.","evidence":"FRAP with ATP/Ran depletion and NUP35 siRNA knockdown across 15 membrane proteins","pmids":["21444689"],"confidence":"High","gaps":["Direct FG–FG interaction between cargo and NUP35 was inferred but not biochemically reconstituted","Contribution of NUP35 FG repeats versus structural role was not separated"]},{"year":2013,"claim":"Mapping of the Ndc1-binding and Nup155-binding sites on NUP35 showed they are functionally separable, and that the Ndc1-binding region overlaps the membrane-bending domain, revealing how NUP35 coordinates membrane remodeling with scaffold recruitment during NPC assembly.","evidence":"Co-immunoprecipitation, in vitro binding, and functional NPC assembly assays in Xenopus egg extract","pmids":["24363447"],"confidence":"High","gaps":["No high-resolution structure of NUP35 in complex with Ndc1 or Nup155","In vivo validation in mammalian somatic cells was limited"]},{"year":2015,"claim":"Discovery that NUP35 selectively exports NHE1 mRNA via its N-terminal domain targeting the 5′-UTR revealed a gene-specific mRNA export function, linking a nucleoporin directly to cardiomyocyte pH homeostasis and ischemic injury.","evidence":"siRNA/overexpression, mRNA nuclear export assay, and ischemia models in cardiomyocytes","pmids":["26260029"],"confidence":"Medium","gaps":["Direct binding of NUP35 to NHE1 mRNA was not reconstituted with purified components","Whether selectivity for NHE1 involves adaptor proteins was unknown"]},{"year":2016,"claim":"An ENU-induced point mutation in the NUP35 RRM domain caused degenerative colonic smooth muscle myopathy in mice, demonstrating that RRM domain integrity is essential for tissue-specific physiology in vivo.","evidence":"Mouse ENU mutagenesis screen with histopathological analysis of RRM domain mutant","pmids":["27427419"],"confidence":"Medium","gaps":["Molecular mechanism connecting the RRM mutation to smooth muscle degeneration was not resolved","Whether the mutation disrupts RNA binding, dimerization, or both was not determined"]},{"year":2018,"claim":"NUP35 was found to relocalize from the nuclear envelope to the meiotic spindle during oocyte maturation and to be required for spindle assembly, chromosome alignment, and kinetochore–microtubule attachment, revealing a non-canonical mitotic/meiotic function.","evidence":"Immunofluorescence localization, siRNA knockdown, spindle assembly checkpoint assay in mouse oocytes","pmids":["30195030"],"confidence":"Medium","gaps":["Mechanism by which NUP35 promotes spindle assembly is unknown","Whether NUP35 phosphorylation at GVBD is required for spindle localization was not tested","Single lab study; independent replication needed"]},{"year":2022,"claim":"Rapid auxin-mediated depletion demonstrated that NUP35, unlike NUP93, has no direct role in gene transcription or 3D genome organization, delimiting its function to transport rather than chromatin regulation.","evidence":"Auxin-inducible degron depletion in human cells with Cut&Run, Hi-C, and HiChIP","pmids":["36323253"],"confidence":"High","gaps":["Whether NUP35 depletion affects mRNA export globally was not assessed in this study","Long-term depletion effects were not characterized"]},{"year":2023,"claim":"NUP35 FG motifs were shown to directly engage HIV-1 capsid in a cyclophilin A–dependent manner, identifying NUP35 as a docking site exploited by the virus for nuclear entry.","evidence":"Direct binding assay of FG-motif regions with HIV-1 CA, siRNA knockdown reducing nuclear entry, CypA mutant analysis","pmids":["37355754"],"confidence":"Medium","gaps":["Relative contribution of NUP35 versus other FG-nucleoporins to HIV-1 entry not quantified","Structural basis of the NUP35 FG–capsid interaction is unresolved"]},{"year":2025,"claim":"Cardiac-specific NUP35 knockout established that NUP35 directly binds Wif1 mRNA and controls its nuclear retention/export, thereby modulating WNT signaling and cardiac fibrosis, confirming NUP35 as a selective mRNA gatekeeper in heart pathophysiology.","evidence":"Cardiac-specific knockout/overexpression mouse models, RIP-seq for direct RNA binding, AAV9-Wif1 rescue","pmids":["41145234"],"confidence":"High","gaps":["Whether NUP35 RNA targets beyond NHE1 and Wif1 share a common cis-element is unknown","Contribution of the RRM domain versus other regions to Wif1 mRNA binding was not dissected"]},{"year":null,"claim":"A unifying model explaining how NUP35 selects specific mRNA substrates for nuclear export—including the role of the RRM domain, potential adaptor proteins, and whether selectivity is tissue-specific—remains to be established.","evidence":"","pmids":[],"confidence":"High","gaps":["No transcriptome-wide map of NUP35-dependent mRNA export in multiple tissue contexts","No structural model of NUP35 in the context of the assembled human inner ring","Mechanism of NUP35 function at the meiotic spindle is uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,7,13]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2,3,6]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[1,3,6,10]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[2,3,4,6]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[7,13]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[10]}],"complexes":["Nuclear pore complex (NPC) inner ring"],"partners":["NDC1","NUP155","NUP93","NUP205"],"other_free_text":[]},"mechanistic_narrative":"NUP35 is an inner-ring nucleoporin that scaffolds nuclear pore complex (NPC) assembly and selectively controls mRNA export to regulate tissue-specific physiology. Its atypical RRM domain forms homodimers through hydrophobic contacts and is required for smooth muscle integrity in vivo [PMID:16962612, PMID:27427419]. NUP35 directly binds Ndc1 and Nup155 to anchor the NPC membrane and recruit the Nup93-containing scaffold; loss of NUP35 blocks NPC assembly and nuclear lamina formation without affecting initial membrane or Nup107 recruitment to chromatin [PMID:16600873, PMID:24363447, PMID:19146848]. Beyond its structural role, NUP35 selectively exports specific mRNAs—including NHE1 and Wif1—to regulate cardiomyocyte pH homeostasis and WNT-dependent cardiac remodeling, while rapid depletion shows it does not broadly control transcription or 3D genome organization [PMID:26260029, PMID:41145234, PMID:36323253]."},"prefetch_data":{"uniprot":{"accession":"Q8NFH5","full_name":"Nucleoporin NUP35","aliases":["35 kDa nucleoporin","Mitotic phosphoprotein 44","MP-44","Nuclear pore complex protein Nup53","Nucleoporin NUP53"],"length_aa":326,"mass_kda":34.8,"function":"Functions as a component of the nuclear pore complex (NPC). NPC components, collectively referred to as nucleoporins (NUPs), can play the role of both NPC structural components and of docking or interaction partners for transiently associated nuclear transport factors. May play a role in the association of MAD1 with the NPC","subcellular_location":"Nucleus, nuclear pore complex; Nucleus membrane","url":"https://www.uniprot.org/uniprotkb/Q8NFH5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NUP35","classification":"Common Essential","n_dependent_lines":589,"n_total_lines":1208,"dependency_fraction":0.48758278145695366},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000163002","cell_line_id":"CID000092","localizations":[{"compartment":"nuclear_membrane","grade":3},{"compartment":"big_aggregates","grade":2}],"interactors":[{"gene":"MAPRE1","stoichiometry":0.2},{"gene":"NUMA1","stoichiometry":0.2},{"gene":"RAB23","stoichiometry":0.2},{"gene":"RAN","stoichiometry":0.2},{"gene":"RANBP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000092","total_profiled":1310},"omim":[{"mim_id":"614352","title":"NUCLEOPORIN, 205-KD; NUP205","url":"https://www.omim.org/entry/614352"},{"mim_id":"614351","title":"NUCLEOPORIN, 93-KD; NUP93","url":"https://www.omim.org/entry/614351"},{"mim_id":"613220","title":"TRANSMEMBRANE PROTEIN 18; TMEM18","url":"https://www.omim.org/entry/613220"},{"mim_id":"610115","title":"NDC1 TRANSMEMBRANE NUCLEOPORIN; NDC1","url":"https://www.omim.org/entry/610115"},{"mim_id":"608140","title":"NUCLEOPORIN, 35-KD; NUP35","url":"https://www.omim.org/entry/608140"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear membrane","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NUP35"},"hgnc":{"alias_symbol":["MP44"],"prev_symbol":[]},"alphafold":{"accession":"Q8NFH5","domains":[{"cath_id":"3.30.70.330","chopping":"174-247","consensus_level":"high","plddt":95.8586,"start":174,"end":247}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NFH5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NFH5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NFH5-F1-predicted_aligned_error_v6.png","plddt_mean":63.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NUP35","jax_strain_url":"https://www.jax.org/strain/search?query=NUP35"},"sequence":{"accession":"Q8NFH5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NFH5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NFH5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NFH5"}},"corpus_meta":[{"pmid":"21444689","id":"PMC_21444689","title":"System analysis shows distinct 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mediates hydrophobic interactions (Met236 sandwiched by Phe178 and Trp209 from the opposing monomer); homodimerization confirmed by analytical ultracentrifugation.\",\n      \"method\": \"X-ray crystallography + analytical ultracentrifugation\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with multiple orthogonal validations in a single study\",\n      \"pmids\": [\"16962612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In C. elegans, Nup35/NPP-19 is required for NE localization of Nup155/NPP-8 and NPC assembly; its depletion causes chromosome missegregation, nuclear morphology defects, and impaired nucleo-cytoplasmic transport, while nuclear membrane targeting and Nup107 recruitment remain NPP-19-independent.\",\n      \"method\": \"Temperature-sensitive mutant analysis, RNAi depletion, immunofluorescence, live imaging in C. elegans embryos\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with multiple defined cellular phenotypes and pathway placement, replicated by orthogonal methods\",\n      \"pmids\": [\"19146848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Nup35 is required for a Ran-dependent translocation mechanism used by a subset of inner nuclear membrane proteins; addition of FG repeats to membrane proteins accelerates their FRAP recovery, and this effect also depends on Nup35, placing Nup35 as a mediator of FG-dependent peripheral channel transport.\",\n      \"method\": \"FRAP after Ran depletion and ATP depletion, siRNA knockdown of Nup35, live cell imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — FRAP with multiple depletions and functional rescue, replicated across 15 proteins\",\n      \"pmids\": [\"21444689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Nup53 (vertebrate ortholog closely related to Nup35) interacts with the integral pore membrane protein Ndc1 through a region that overlaps with membrane-bending activity, and also interacts with Nup155 as the main determinant of Nup155 recruitment to assembling NPCs; both interactions are essential for vertebrate NPC assembly.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, siRNA depletion, in vitro membrane-bending assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with functional rescue, multiple interaction modes dissected\",\n      \"pmids\": [\"24363447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nup35 regulates NHE1 (Na+/H+ exchanger-1) expression in cardiomyocytes by controlling nucleo-cytoplasmic trafficking of nhe1 mRNA; the N-terminal domain of Nup35 is required for nhe1 mRNA nuclear export by targeting the 5'-UTR (-412 to -213 nt) of nhe1 mRNA. Nup35 ablation depresses NHE1 expression and weakens resistance to acid challenge.\",\n      \"method\": \"siRNA knockdown, mRNA export assay, domain deletion analysis, intracellular pH measurement, enforced expression rescue\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined molecular mechanism, single lab\",\n      \"pmids\": [\"26260029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A point mutation in the RNA recognition motif of Nup35 in mice causes a degenerative myopathy specifically affecting colonic smooth muscle, leading to megacolon and reduced lifespan, demonstrating that RRM domain integrity is required for Nup35 function in smooth muscle.\",\n      \"method\": \"ENU mutagenesis mouse model, histopathology, immunohistochemistry\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined in vivo loss-of-function with specific tissue phenotype, single lab\",\n      \"pmids\": [\"27427419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Stoichiometry of Nup35 within the nuclear pore complex was measured at approximately 23 copies per NPC using single-molecule GFP fluorescence standards under spinning disk confocal microscopy.\",\n      \"method\": \"Single-molecule fluorescence quantification, GFP-based stoichiometry assay with endogenous knockdown/replacement\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative imaging with knockdown-replacement strategy, single lab\",\n      \"pmids\": [\"27613095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In mouse oocytes, Nup35 localizes to microtubules and the spindle during meiosis (but not at GV stage), undergoes phosphorylation after resumption of meiosis (GVBD), and is required for spindle assembly, chromosome alignment, and first polar body extrusion; knockdown causes defective kinetochore-microtubule attachment and activates the spindle assembly checkpoint, with p-ERK1/2 displaced from spindle poles.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, phosphorylation analysis, spindle assembly checkpoint assay in mouse oocytes\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotypes and pathway placement, single lab\",\n      \"pmids\": [\"30195030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Acute auxin-mediated depletion of NUP35 in human cells shows that NUP35 does not directly control gene transcription (in contrast to NUP93), and NUP35 depletion causes negligible changes in 3D genome organization including A/B compartments, TADs, and enhancer-promoter contacts.\",\n      \"method\": \"Auxin-inducible degron rapid depletion, Cut&Run, in situ Hi-C, HiChIP\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — acute depletion with multiple genomic readouts, single lab\",\n      \"pmids\": [\"36323253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HIV-1 capsid (CA) directly interacts with Nup35 via regions containing FG motifs, and Nup35 (together with Nup153 and POM121) coordinately supports HIV-1 nuclear entry; this dependence on Nup35 requires cyclophilin A (CypA) interaction with CA.\",\n      \"method\": \"siRNA knockdown, direct binding assays, CA mutant analysis, soluble host factor depletion\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction mapped with mutants and functional knockdown, single study\",\n      \"pmids\": [\"37355754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nup35 directly binds Wif1 mRNA (assessed by RNA immunoprecipitation sequencing), retaining Wif1 pre-mRNA in the nucleus and reducing Wif1 protein levels; cardiac-specific Nup35 knockout causes severe fibrosis, hypertrophy, and dysfunction reversed by AAV9-delivered Wif1 mRNA, placing Nup35 upstream of Wnt inhibitory signaling in cardiomyocytes.\",\n      \"method\": \"Cardiac-specific knockout and overexpression mouse models, RNA immunoprecipitation sequencing (RIP-seq), AAV9 rescue experiment\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vivo KO with RIP-seq mechanistic identification and rescue, multiple orthogonal methods\",\n      \"pmids\": [\"41145234\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUP35 is an NPC scaffold nucleoporin (~23 copies/pore) whose RRM domain forms homodimers and whose N-terminal domain facilitates FG-dependent peripheral channel translocation of inner nuclear membrane proteins in a Ran-dependent manner; it is essential for NPC assembly by recruiting Nup155 to the forming pore, acts as an mRNA export factor for select transcripts (nhe1 mRNA, Wif1 mRNA) through direct mRNA binding, functions as a microtubule-associated protein required for meiotic spindle assembly, and provides direct docking sites for HIV-1 capsid FG-motif interactions during nuclear entry.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"The crystal structure of the RRM domain of mouse Nup35 was solved at 2.7 Å resolution, revealing an atypical betaalphabetabetaalphabeta topology with non-canonical RNP1 and RNP2 motifs. The RRM domain forms a homodimer both in crystal and in solution (analytical ultracentrifugation), with homodimerization driven primarily by hydrophobic interactions involving Met236 (beta4), Phe178 (beta1), and Trp209 (beta3).\",\n      \"method\": \"X-ray crystallography (2.7 Å) + analytical ultracentrifugation\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with orthogonal solution-phase validation by analytical ultracentrifugation\",\n      \"pmids\": [\"16962612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"NUP35 (Nup53) was identified as a component of the mammalian nuclear pore complex proteome, establishing its identity as a nucleoporin.\",\n      \"method\": \"Biochemical purification of NPC fraction + mass spectrometry\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — proteomic identification from purified NPC fraction, widely replicated\",\n      \"pmids\": [\"12196509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"NDC1, a transmembrane nucleoporin, directly interacts with Nup53 (NUP35) in vitro, linking the NE membrane to soluble nucleoporins during NPC assembly. RNAi of NDC1 phenocopies depletion of Nup93, Nup53, and Nup205, placing NDC1 and Nup53 in the same functional pathway for NPC assembly.\",\n      \"method\": \"In vitro binding assay + RNAi epistasis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct in vitro interaction combined with genetic epistasis by RNAi\",\n      \"pmids\": [\"16600873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In vivo loss-of-function of Nup35/NPP-19 in C. elegans (npp-19(tm2886) mutant) causes chromosome missegregation, nuclear morphology defects, and embryonic lethality. Depletion of Nup35/NPP-19 specifically blocks NE localization of Nup155/NPP-8, NPC assembly, and nuclear lamina formation, while nuclear membrane targeting and Nup107/NPP-5 recruitment to chromatin remain Nup35-independent, indicating Nup35 acts downstream of membrane recruitment but upstream of NPC scaffold assembly.\",\n      \"method\": \"C. elegans genetic loss-of-function (temperature-sensitive allele) + immunofluorescence localization of NPC components\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic loss-of-function with specific phenotypic readouts and epistasis for multiple NPC components\",\n      \"pmids\": [\"19146848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Nup35 is required for the Ran-dependent mechanism of integral membrane protein translocation to the inner nuclear membrane. FG repeats added to membrane proteins reduce FRAP recovery times, and this effect also depends on Nup35, suggesting that Nup35 facilitates FG-mediated transport through the peripheral channels of the NPC.\",\n      \"method\": \"FRAP with ATP/Ran depletion conditions + siRNA knockdown of Nup35\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — FRAP with multiple perturbation conditions (ATP depletion, Ran depletion, Nup35 siRNA) and modeling across 15 proteins\",\n      \"pmids\": [\"21444689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FG repeats on integral membrane proteins facilitate their own transport to the inner nuclear membrane via a mechanism requiring Nup35, which itself contains FG repeats, suggesting these proteins use FG-FG interactions to act as their own nuclear transport receptors through NPC peripheral channels.\",\n      \"method\": \"FG-repeat addition to membrane proteins + FRAP + Nup35 requirement demonstrated by knockdown\",\n      \"journal\": \"Communicative & integrative biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic interpretation supported by FRAP data, but commentary/follow-up paper based on primary FRAP study\",\n      \"pmids\": [\"22046461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Nup53 (NUP35 vertebrate ortholog in Xenopus/vertebrate context) interacts with Ndc1 and Nup155. The Ndc1-binding site on Nup53 overlaps with its membrane-bending region, and this interaction modulates membrane-deforming activity. Nup53-Nup155 interaction is the main determinant for recruiting Nup155 to the assembling NPC. Disruption of either interaction blocks vertebrate NPC assembly.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assays, RNAi depletion with NPC assembly phenotype readout\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (biochemical binding, RNAi, functional NPC assembly assay) in single study\",\n      \"pmids\": [\"24363447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NUP35 regulates cardiomyocyte pH homeostasis by controlling nucleo-cytoplasmic trafficking of NHE1 (nhe1) mRNA. The N-terminal domain of NUP35 mediates nhe1 mRNA nuclear export by targeting the 5'-UTR (-412 to -213 nt) of nhe1 mRNA. NUP35 ablation reduces NHE1 expression and weakens resistance to acid challenge. NUP35 and NHE1 are co-downregulated in ischemic cardiomyocytes, and enforced NUP35 expression counteracts anoxia-induced acidification.\",\n      \"method\": \"siRNA knockdown, overexpression, mRNA export assay, in vivo/in vitro ischemia model\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple functional assays but mechanism of RNA targeting is based on domain deletion rather than direct binding reconstitution\",\n      \"pmids\": [\"26260029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A point mutation in the RNA recognition motif of Nup35 in mice causes a degenerative myopathy specifically affecting colonic smooth muscle, leading to megacolon and reduced lifespan, demonstrating that Nup35 RRM domain function is required for smooth muscle integrity in vivo.\",\n      \"method\": \"ENU point mutation in mouse Nup35 RRM domain; histopathological analysis\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model with specific tissue phenotype, but molecular mechanism not fully resolved\",\n      \"pmids\": [\"27427419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The stoichiometry of Nup35 within the human NPC was experimentally estimated at approximately 23 copies per nuclear pore complex using a GFP single-molecule fluorescence standard with endogenous knockdown and GFP-knockdown-resistant replacement.\",\n      \"method\": \"Quantitative single-molecule fluorescence microscopy with spinning disk confocal + knockdown/replacement approach\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct quantitative measurement with appropriate controls for copy number determination\",\n      \"pmids\": [\"27613095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Nup35 dynamically relocalizes during oocyte meiosis: it resides at the nuclear membrane at the germinal vesicle (GV) stage, then redistributes to microtubules and the spindle during pro-MI, MI, and MII, and to spindle poles at AI and TI. Nup35 appears in a phosphorylated form after meiotic resumption (GVBD). siRNA knockdown of Nup35 impairs first polar body extrusion, spindle assembly, chromosome alignment, and kinetochore-microtubule attachment, and activates the spindle assembly checkpoint. Knockdown also dissociates p-ERK1/2 from spindle poles.\",\n      \"method\": \"Immunofluorescence localization, siRNA knockdown, spindle assembly checkpoint activation assay, phosphorylation detection by Western blot\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct localization with functional consequence, siRNA KD with multiple specific phenotypic readouts, but single lab study\",\n      \"pmids\": [\"30195030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Rapid auxin-mediated depletion of NUP35 in human cells demonstrates that NUP35, unlike NUP93, does not directly control gene transcription. NUP35 depletion causes no significant changes in gene expression, 3D genome organization (A/B compartments, TADs), or enhancer-promoter contacts as measured by Hi-C and HiChIP.\",\n      \"method\": \"Auxin-inducible degron rapid depletion + Cut&Run + Hi-C + HiChIP\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — rapid depletion with multiple orthogonal genome-wide assays, rigorous controls\",\n      \"pmids\": [\"36323253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nup35 makes direct physical interactions with HIV-1 capsid (CA) via regions containing FG motifs, supporting HIV-1 nuclear entry. This interaction is dependent on cyclophilin A (CypA) interaction with CA. Knockdown of Nup35 reduces HIV-1 nuclear entry efficiency, placing Nup35 among NPC components that the HIV-1 capsid core exploits as a macromolecular nuclear transport receptor.\",\n      \"method\": \"siRNA knockdown of Nup35 + direct binding assay of FG motifs with HIV-1 CA + CypA mutant analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding demonstrated with FG motif regions, functional KD phenotype in viral nuclear entry\",\n      \"pmids\": [\"37355754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cardiac-specific Nup35 knockout mice develop severe cardiac fibrosis, hypertrophy, and dysfunction; Nup35 overexpression is protective. Mechanistically, Nup35 directly binds Wif1 mRNA (shown by RNA immunoprecipitation sequencing), retaining pre-mRNA of Wif1 in the nucleus and decreasing Wif1 protein in Nup35-deficient cardiomyocytes. AAV9-mediated Wif1 restoration rescues the cardiac phenotype of Nup35 knockout mice, placing Nup35 upstream of Wif1 in the WNT pathway during pathological cardiac remodeling.\",\n      \"method\": \"Cardiac-specific knockout/overexpression mouse models + RNA immunoprecipitation sequencing (RIP-seq) + AAV9 rescue\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vivo genetic KO/OE with specific phenotype, direct RNA binding shown by RIP-seq, epistasis established by AAV rescue\",\n      \"pmids\": [\"41145234\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUP35 is a nucleoporin of the NPC inner ring whose RRM domain forms homodimers and binds mRNA; it physically interacts with Ndc1, Nup155, and Nup93 to scaffold NPC assembly and anchor the pore membrane, facilitates Ran-dependent FG-mediated translocation of integral proteins to the inner nuclear membrane, selectively controls nuclear export of specific mRNAs (including NHE1 and Wif1) to regulate cardiomyocyte pH homeostasis and WNT signaling in cardiac remodeling, localizes to the meiotic spindle where it supports spindle assembly and chromosome segregation, and provides FG-motif-dependent docking sites for HIV-1 capsid during nuclear entry.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NUP35 is a scaffold nucleoporin (~23 copies per NPC) that plays essential roles in nuclear pore complex assembly, selective mRNA export, and meiotic spindle organization. Its RRM domain mediates homodimerization through an atypical beta-sheet interface, and its N-terminal region recruits Nup155 and interacts with the transmembrane nucleoporin Ndc1 to drive NPC assembly; it also facilitates Ran-dependent, FG-motif-dependent translocation of inner nuclear membrane proteins through the pore's peripheral channels [PMID:16962612, PMID:19146848, PMID:24363447, PMID:21444689]. NUP35 directly binds select mRNAs—including nhe1 and Wif1—to regulate their nuclear export, thereby controlling NHE1-dependent acid resistance in cardiomyocytes and Wnt-inhibitory signaling that prevents cardiac fibrosis and hypertrophy [PMID:26260029, PMID:41145234]. During meiosis in oocytes, NUP35 relocalizes to microtubules and the spindle, where it is required for proper kinetochore–microtubule attachment, chromosome alignment, and polar body extrusion [PMID:30195030].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Determining how NUP35 self-assembles was unknown; crystallography revealed that the RRM domain homodimerizes via an atypical beta-sheet interface rather than through canonical RNA-binding surfaces, establishing the structural basis for NUP35 oligomerization within the NPC scaffold.\",\n      \"evidence\": \"X-ray crystallography at 2.7 Å and analytical ultracentrifugation of mouse Nup35 RRM domain\",\n      \"pmids\": [\"16962612\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether homodimerization is required for NPC incorporation was not tested\",\n        \"Full-length NUP35 structure remains unsolved\",\n        \"RNA-binding capacity of the atypical RRM was not assessed\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The role of NUP35 in NPC assembly was undefined; loss-of-function in C. elegans showed that NUP35/NPP-19 is specifically required to recruit Nup155 to pores and for proper NPC assembly, while Nup107 recruitment and membrane targeting are NUP35-independent, establishing NUP35 as a linker nucleoporin with selective recruitment activity.\",\n      \"evidence\": \"Temperature-sensitive mutant and RNAi depletion with immunofluorescence and live imaging in C. elegans embryos\",\n      \"pmids\": [\"19146848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct physical interaction between NUP35 and Nup155 was not demonstrated in this system\",\n        \"Whether NUP35's NPC assembly role is conserved in vertebrates was not shown\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"How inner nuclear membrane proteins traverse the NPC peripheral channel was unclear; FRAP-based depletion studies showed NUP35 is required for Ran-dependent, FG-motif-facilitated translocation of INM proteins, defining NUP35 as a gatekeeper of the peripheral transport route.\",\n      \"evidence\": \"FRAP after Ran/ATP depletion and siRNA knockdown of NUP35 across 15 INM proteins in live cells\",\n      \"pmids\": [\"21444689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether NUP35 directly contacts transiting INM proteins or acts indirectly was not resolved\",\n        \"The structural basis for NUP35's role in peripheral channel gating is unknown\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The vertebrate NPC assembly mechanism required identification of direct NUP35 interaction partners; biochemical dissection showed that Nup53 (vertebrate NUP35-related) binds both transmembrane Ndc1 and Nup155 through distinct regions, and both interactions are essential for pore assembly, confirming NUP35 as a central bridging nucleoporin.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, pulldowns, siRNA depletion and in vitro membrane-bending assays\",\n      \"pmids\": [\"24363447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Nup35 versus Nup53 paralog functions are fully redundant in vertebrates is unclear\",\n        \"Structural details of the Ndc1–NUP35 interface are not resolved\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Whether NUP35 has transcript-selective mRNA export functions was unknown; knockdown and domain-deletion studies in cardiomyocytes revealed that NUP35's N-terminal domain controls nuclear export of nhe1 mRNA by targeting its 5′-UTR, establishing NUP35 as a selective mRNA export factor.\",\n      \"evidence\": \"siRNA knockdown, mRNA export assay, domain deletion, intracellular pH measurement, and rescue in cardiomyocytes\",\n      \"pmids\": [\"26260029\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether NUP35 directly binds nhe1 mRNA or acts via adaptor proteins was not shown\",\n        \"Generalizability of this mRNA export role beyond nhe1 was not assessed\",\n        \"Single-lab finding\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The in vivo consequence of RRM domain disruption was unknown; an ENU-induced point mutation in the NUP35 RRM caused degenerative colonic smooth muscle myopathy and megacolon in mice, demonstrating tissue-specific dependence on RRM integrity.\",\n      \"evidence\": \"ENU mutagenesis mouse model with histopathology and immunohistochemistry\",\n      \"pmids\": [\"27427419\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular mechanism linking RRM disruption to smooth muscle degeneration is uncharacterized\",\n        \"Whether this reflects loss of RNA binding, homodimerization, or NPC assembly is unknown\",\n        \"Single-lab study\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"NUP35 copy number per NPC was uncertain; quantitative single-molecule fluorescence established ~23 copies per pore, providing a stoichiometric constraint for NPC architectural models.\",\n      \"evidence\": \"Single-molecule GFP fluorescence with endogenous knockdown/replacement under spinning disk confocal\",\n      \"pmids\": [\"27613095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether copy number varies across cell types or during the cell cycle was not tested\",\n        \"Single-lab measurement\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"NUP35 was known only as a nucleoporin; its relocation to microtubules and the meiotic spindle after GVBD, and the requirement for proper kinetochore–microtubule attachment, spindle assembly, and polar body extrusion in oocytes, revealed an unexpected NPC-independent function as a spindle-associated protein.\",\n      \"evidence\": \"siRNA knockdown, immunofluorescence, phosphorylation analysis, and spindle assembly checkpoint assay in mouse oocytes\",\n      \"pmids\": [\"30195030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether NUP35 directly binds tubulin or associates via adaptor proteins is unknown\",\n        \"Relevance to mitotic (somatic) spindle assembly not tested\",\n        \"Single-lab study\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Whether NUP35 directly regulates transcription or 3D genome organization was untested; acute auxin-mediated depletion showed negligible effects on gene expression and chromatin architecture, distinguishing NUP35 from its NUP93 complex partner and indicating its primary roles lie elsewhere.\",\n      \"evidence\": \"Auxin-inducible degron depletion with Cut&Run, in situ Hi-C, and HiChIP in human cells\",\n      \"pmids\": [\"36323253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Long-term or cell-type-specific transcriptional roles cannot be excluded by acute depletion\",\n        \"Potential post-transcriptional (mRNA export) effects were not measured in this study\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"How HIV-1 capsid engages the NPC for nuclear entry was incompletely mapped; direct binding assays showed CA interacts with NUP35 FG motifs in a CypA-dependent manner, identifying NUP35 as a docking site for viral nuclear import alongside Nup153 and POM121.\",\n      \"evidence\": \"siRNA knockdown, direct binding assays, CA mutant panel, and soluble factor depletion\",\n      \"pmids\": [\"37355754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis of CA–NUP35 FG interaction not resolved\",\n        \"Relative contribution of NUP35 versus other FG-nucleoporins to HIV-1 nuclear entry is unclear\",\n        \"Single study\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether NUP35's mRNA export function extends beyond nhe1 was unknown; RIP-seq and cardiac-specific knockout identified Wif1 mRNA as a direct NUP35 target whose nuclear retention by NUP35 suppresses Wif1 protein and thereby sustains Wnt signaling, with loss of NUP35 causing severe cardiac fibrosis reversed by exogenous Wif1, establishing a NUP35–Wif1–Wnt axis in the heart.\",\n      \"evidence\": \"Cardiac-specific knockout and overexpression mouse models, RIP-seq, AAV9-Wif1 rescue\",\n      \"pmids\": [\"41145234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full repertoire of NUP35-bound transcripts beyond nhe1 and Wif1 is not characterized\",\n        \"Whether NUP35 retains Wif1 mRNA in the nucleus by blocking export or promoting degradation is not fully resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis for NUP35's selective mRNA binding and export, whether its spindle-associated function in meiosis extends to mitosis, and the molecular mechanism linking RRM domain integrity to smooth muscle homeostasis.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No full-length NUP35 structure or NUP35–RNA co-structure exists\",\n        \"Spindle function has only been shown in oocyte meiosis, not somatic mitosis\",\n        \"Mechanism of tissue-specific pathology from RRM mutations is uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 4, 10]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 3, 6]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [1, 2, 3, 6]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2, 4, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 2, 3, 4, 10]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\n      \"NUP93 complex\",\n      \"Nuclear pore complex\"\n    ],\n    \"partners\": [\n      \"NUP155\",\n      \"NDC1\",\n      \"NUP93\",\n      \"NUP153\",\n      \"POM121\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"NUP35 is an inner-ring nucleoporin that scaffolds nuclear pore complex (NPC) assembly and selectively controls mRNA export to regulate tissue-specific physiology. Its atypical RRM domain forms homodimers through hydrophobic contacts and is required for smooth muscle integrity in vivo [PMID:16962612, PMID:27427419]. NUP35 directly binds Ndc1 and Nup155 to anchor the NPC membrane and recruit the Nup93-containing scaffold; loss of NUP35 blocks NPC assembly and nuclear lamina formation without affecting initial membrane or Nup107 recruitment to chromatin [PMID:16600873, PMID:24363447, PMID:19146848]. Beyond its structural role, NUP35 selectively exports specific mRNAs—including NHE1 and Wif1—to regulate cardiomyocyte pH homeostasis and WNT-dependent cardiac remodeling, while rapid depletion shows it does not broadly control transcription or 3D genome organization [PMID:26260029, PMID:41145234, PMID:36323253].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing NUP35 as a bona fide component of the mammalian NPC resolved its identity as a nucleoporin and placed it within the pore proteome for subsequent mechanistic dissection.\",\n      \"evidence\": \"Biochemical purification of NPC fraction coupled with mass spectrometry\",\n      \"pmids\": [\"12196509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Position within the NPC substructure was not defined\",\n        \"No interaction partners identified at this stage\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Solving the crystal structure of the NUP35 RRM domain revealed an atypical RNA-recognition fold that homodimerizes through specific hydrophobic contacts, providing the first structural framework for understanding its dual roles in self-assembly and RNA binding.\",\n      \"evidence\": \"X-ray crystallography at 2.7 Å of mouse Nup35 RRM domain with analytical ultracentrifugation\",\n      \"pmids\": [\"16962612\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"RNA substrates recognized by the RRM domain were not identified\",\n        \"Functional consequences of homodimerization in NPC context were untested\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that the transmembrane nucleoporin Ndc1 directly binds NUP35 in vitro and that RNAi of either protein produces equivalent NPC assembly defects established the Ndc1–NUP35 axis as a membrane-to-scaffold bridge during pore biogenesis.\",\n      \"evidence\": \"In vitro binding assay and RNAi epistasis in mammalian cells\",\n      \"pmids\": [\"16600873\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the Ndc1–NUP35 interface was unknown\",\n        \"Whether Ndc1 binding modulates NUP35 membrane deformation was untested\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genetic loss-of-function in C. elegans placed NUP35 downstream of nuclear membrane recruitment but upstream of Nup155 and full NPC scaffold assembly, defining its hierarchical position in pore biogenesis.\",\n      \"evidence\": \"C. elegans npp-19 temperature-sensitive mutant with immunofluorescence of NPC component localization\",\n      \"pmids\": [\"19146848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether this hierarchy is conserved in vertebrate post-mitotic NPC assembly was not confirmed\",\n        \"Molecular basis for NUP35-dependent Nup155 recruitment was undefined\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"NUP35 was shown to be required for Ran-dependent translocation of integral membrane proteins to the inner nuclear membrane via FG-repeat interactions, extending its function beyond scaffold assembly to active gating of peripheral NPC channels.\",\n      \"evidence\": \"FRAP with ATP/Ran depletion and NUP35 siRNA knockdown across 15 membrane proteins\",\n      \"pmids\": [\"21444689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct FG–FG interaction between cargo and NUP35 was inferred but not biochemically reconstituted\",\n        \"Contribution of NUP35 FG repeats versus structural role was not separated\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapping of the Ndc1-binding and Nup155-binding sites on NUP35 showed they are functionally separable, and that the Ndc1-binding region overlaps the membrane-bending domain, revealing how NUP35 coordinates membrane remodeling with scaffold recruitment during NPC assembly.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro binding, and functional NPC assembly assays in Xenopus egg extract\",\n      \"pmids\": [\"24363447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of NUP35 in complex with Ndc1 or Nup155\",\n        \"In vivo validation in mammalian somatic cells was limited\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery that NUP35 selectively exports NHE1 mRNA via its N-terminal domain targeting the 5′-UTR revealed a gene-specific mRNA export function, linking a nucleoporin directly to cardiomyocyte pH homeostasis and ischemic injury.\",\n      \"evidence\": \"siRNA/overexpression, mRNA nuclear export assay, and ischemia models in cardiomyocytes\",\n      \"pmids\": [\"26260029\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding of NUP35 to NHE1 mRNA was not reconstituted with purified components\",\n        \"Whether selectivity for NHE1 involves adaptor proteins was unknown\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"An ENU-induced point mutation in the NUP35 RRM domain caused degenerative colonic smooth muscle myopathy in mice, demonstrating that RRM domain integrity is essential for tissue-specific physiology in vivo.\",\n      \"evidence\": \"Mouse ENU mutagenesis screen with histopathological analysis of RRM domain mutant\",\n      \"pmids\": [\"27427419\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular mechanism connecting the RRM mutation to smooth muscle degeneration was not resolved\",\n        \"Whether the mutation disrupts RNA binding, dimerization, or both was not determined\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"NUP35 was found to relocalize from the nuclear envelope to the meiotic spindle during oocyte maturation and to be required for spindle assembly, chromosome alignment, and kinetochore–microtubule attachment, revealing a non-canonical mitotic/meiotic function.\",\n      \"evidence\": \"Immunofluorescence localization, siRNA knockdown, spindle assembly checkpoint assay in mouse oocytes\",\n      \"pmids\": [\"30195030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which NUP35 promotes spindle assembly is unknown\",\n        \"Whether NUP35 phosphorylation at GVBD is required for spindle localization was not tested\",\n        \"Single lab study; independent replication needed\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Rapid auxin-mediated depletion demonstrated that NUP35, unlike NUP93, has no direct role in gene transcription or 3D genome organization, delimiting its function to transport rather than chromatin regulation.\",\n      \"evidence\": \"Auxin-inducible degron depletion in human cells with Cut&Run, Hi-C, and HiChIP\",\n      \"pmids\": [\"36323253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether NUP35 depletion affects mRNA export globally was not assessed in this study\",\n        \"Long-term depletion effects were not characterized\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"NUP35 FG motifs were shown to directly engage HIV-1 capsid in a cyclophilin A–dependent manner, identifying NUP35 as a docking site exploited by the virus for nuclear entry.\",\n      \"evidence\": \"Direct binding assay of FG-motif regions with HIV-1 CA, siRNA knockdown reducing nuclear entry, CypA mutant analysis\",\n      \"pmids\": [\"37355754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Relative contribution of NUP35 versus other FG-nucleoporins to HIV-1 entry not quantified\",\n        \"Structural basis of the NUP35 FG–capsid interaction is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cardiac-specific NUP35 knockout established that NUP35 directly binds Wif1 mRNA and controls its nuclear retention/export, thereby modulating WNT signaling and cardiac fibrosis, confirming NUP35 as a selective mRNA gatekeeper in heart pathophysiology.\",\n      \"evidence\": \"Cardiac-specific knockout/overexpression mouse models, RIP-seq for direct RNA binding, AAV9-Wif1 rescue\",\n      \"pmids\": [\"41145234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether NUP35 RNA targets beyond NHE1 and Wif1 share a common cis-element is unknown\",\n        \"Contribution of the RRM domain versus other regions to Wif1 mRNA binding was not dissected\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unifying model explaining how NUP35 selects specific mRNA substrates for nuclear export—including the role of the RRM domain, potential adaptor proteins, and whether selectivity is tissue-specific—remains to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No transcriptome-wide map of NUP35-dependent mRNA export in multiple tissue contexts\",\n        \"No structural model of NUP35 in the context of the assembled human inner ring\",\n        \"Mechanism of NUP35 function at the meiotic spindle is uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 7, 13]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2, 3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [1, 3, 6, 10]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0009536\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2, 3, 4, 6]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [7, 13]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\n      \"Nuclear pore complex (NPC) inner ring\"\n    ],\n    \"partners\": [\n      \"NDC1\",\n      \"NUP155\",\n      \"NUP93\",\n      \"NUP205\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I included a spurious plastid localization entry. Let me fix the pathway section — I need to remove that erroneous GO:0009536 entry.\n\n```json\n{\n  \"mechanistic_narrative\": \"NUP35 is an inner-ring nucleoporin that scaffolds nuclear pore complex (NPC) assembly and selectively controls mRNA export to regulate tissue-specific physiology. Its atypical RRM domain forms homodimers through hydrophobic contacts and is required for smooth muscle integrity in vivo [PMID:16962612, PMID:27427419]. NUP35 directly binds Ndc1 and Nup155 to anchor the NPC membrane and recruit the Nup93-containing scaffold; loss of NUP35 blocks NPC assembly and nuclear lamina formation without affecting initial membrane or Nup107 recruitment to chromatin [PMID:16600873, PMID:24363447, PMID:19146848]. Beyond its structural role, NUP35 selectively exports specific mRNAs—including NHE1 and Wif1—to regulate cardiomyocyte pH homeostasis and WNT-dependent cardiac remodeling, while rapid depletion shows it does not broadly control transcription or 3D genome organization [PMID:26260029, PMID:41145234, PMID:36323253].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing NUP35 as a bona fide component of the mammalian NPC resolved its identity as a nucleoporin and placed it within the pore proteome for subsequent mechanistic dissection.\",\n      \"evidence\": \"Biochemical purification of NPC fraction coupled with mass spectrometry\",\n      \"pmids\": [\"12196509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Position within the NPC substructure was not defined\",\n        \"No interaction partners identified at this stage\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Solving the crystal structure of the NUP35 RRM domain revealed an atypical RNA-recognition fold that homodimerizes through specific hydrophobic contacts, providing the first structural framework for understanding its dual roles in self-assembly and RNA binding.\",\n      \"evidence\": \"X-ray crystallography at 2.7 Å of mouse Nup35 RRM domain with analytical ultracentrifugation\",\n      \"pmids\": [\"16962612\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"RNA substrates recognized by the RRM domain were not identified\",\n        \"Functional consequences of homodimerization in NPC context were untested\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that the transmembrane nucleoporin Ndc1 directly binds NUP35 in vitro and that RNAi of either protein produces equivalent NPC assembly defects established the Ndc1–NUP35 axis as a membrane-to-scaffold bridge during pore biogenesis.\",\n      \"evidence\": \"In vitro binding assay and RNAi epistasis in mammalian cells\",\n      \"pmids\": [\"16600873\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the Ndc1–NUP35 interface was unknown\",\n        \"Whether Ndc1 binding modulates NUP35 membrane deformation was untested\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genetic loss-of-function in C. elegans placed NUP35 downstream of nuclear membrane recruitment but upstream of Nup155 and full NPC scaffold assembly, defining its hierarchical position in pore biogenesis.\",\n      \"evidence\": \"C. elegans npp-19 temperature-sensitive mutant with immunofluorescence of NPC component localization\",\n      \"pmids\": [\"19146848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether this hierarchy is conserved in vertebrate post-mitotic NPC assembly was not confirmed\",\n        \"Molecular basis for NUP35-dependent Nup155 recruitment was undefined\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"NUP35 was shown to be required for Ran-dependent translocation of integral membrane proteins to the inner nuclear membrane via FG-repeat interactions, extending its function beyond scaffold assembly to active gating of peripheral NPC channels.\",\n      \"evidence\": \"FRAP with ATP/Ran depletion and NUP35 siRNA knockdown across 15 membrane proteins\",\n      \"pmids\": [\"21444689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct FG–FG interaction between cargo and NUP35 was inferred but not biochemically reconstituted\",\n        \"Contribution of NUP35 FG repeats versus structural role was not separated\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapping of the Ndc1-binding and Nup155-binding sites on NUP35 showed they are functionally separable, and that the Ndc1-binding region overlaps the membrane-bending domain, revealing how NUP35 coordinates membrane remodeling with scaffold recruitment during NPC assembly.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro binding, and functional NPC assembly assays in Xenopus egg extract\",\n      \"pmids\": [\"24363447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of NUP35 in complex with Ndc1 or Nup155\",\n        \"In vivo validation in mammalian somatic cells was limited\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery that NUP35 selectively exports NHE1 mRNA via its N-terminal domain targeting the 5′-UTR revealed a gene-specific mRNA export function, linking a nucleoporin directly to cardiomyocyte pH homeostasis and ischemic injury.\",\n      \"evidence\": \"siRNA/overexpression, mRNA nuclear export assay, and ischemia models in cardiomyocytes\",\n      \"pmids\": [\"26260029\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding of NUP35 to NHE1 mRNA was not reconstituted with purified components\",\n        \"Whether selectivity for NHE1 involves adaptor proteins was unknown\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"An ENU-induced point mutation in the NUP35 RRM domain caused degenerative colonic smooth muscle myopathy in mice, demonstrating that RRM domain integrity is essential for tissue-specific physiology in vivo.\",\n      \"evidence\": \"Mouse ENU mutagenesis screen with histopathological analysis of RRM domain mutant\",\n      \"pmids\": [\"27427419\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular mechanism connecting the RRM mutation to smooth muscle degeneration was not resolved\",\n        \"Whether the mutation disrupts RNA binding, dimerization, or both was not determined\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"NUP35 was found to relocalize from the nuclear envelope to the meiotic spindle during oocyte maturation and to be required for spindle assembly, chromosome alignment, and kinetochore–microtubule attachment, revealing a non-canonical mitotic/meiotic function.\",\n      \"evidence\": \"Immunofluorescence localization, siRNA knockdown, spindle assembly checkpoint assay in mouse oocytes\",\n      \"pmids\": [\"30195030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which NUP35 promotes spindle assembly is unknown\",\n        \"Whether NUP35 phosphorylation at GVBD is required for spindle localization was not tested\",\n        \"Single lab study; independent replication needed\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Rapid auxin-mediated depletion demonstrated that NUP35, unlike NUP93, has no direct role in gene transcription or 3D genome organization, delimiting its function to transport rather than chromatin regulation.\",\n      \"evidence\": \"Auxin-inducible degron depletion in human cells with Cut&Run, Hi-C, and HiChIP\",\n      \"pmids\": [\"36323253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether NUP35 depletion affects mRNA export globally was not assessed in this study\",\n        \"Long-term depletion effects were not characterized\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"NUP35 FG motifs were shown to directly engage HIV-1 capsid in a cyclophilin A–dependent manner, identifying NUP35 as a docking site exploited by the virus for nuclear entry.\",\n      \"evidence\": \"Direct binding assay of FG-motif regions with HIV-1 CA, siRNA knockdown reducing nuclear entry, CypA mutant analysis\",\n      \"pmids\": [\"37355754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Relative contribution of NUP35 versus other FG-nucleoporins to HIV-1 entry not quantified\",\n        \"Structural basis of the NUP35 FG–capsid interaction is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cardiac-specific NUP35 knockout established that NUP35 directly binds Wif1 mRNA and controls its nuclear retention/export, thereby modulating WNT signaling and cardiac fibrosis, confirming NUP35 as a selective mRNA gatekeeper in heart pathophysiology.\",\n      \"evidence\": \"Cardiac-specific knockout/overexpression mouse models, RIP-seq for direct RNA binding, AAV9-Wif1 rescue\",\n      \"pmids\": [\"41145234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether NUP35 RNA targets beyond NHE1 and Wif1 share a common cis-element is unknown\",\n        \"Contribution of the RRM domain versus other regions to Wif1 mRNA binding was not dissected\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unifying model explaining how NUP35 selects specific mRNA substrates for nuclear export—including the role of the RRM domain, potential adaptor proteins, and whether selectivity is tissue-specific—remains to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No transcriptome-wide map of NUP35-dependent mRNA export in multiple tissue contexts\",\n        \"No structural model of NUP35 in the context of the assembled human inner ring\",\n        \"Mechanism of NUP35 function at the meiotic spindle is uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 7, 13]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2, 3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [1, 3, 6, 10]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2, 3, 4, 6]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [7, 13]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\n      \"Nuclear pore complex (NPC) inner ring\"\n    ],\n    \"partners\": [\n      \"NDC1\",\n      \"NUP155\",\n      \"NUP93\",\n      \"NUP205\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}