{"gene":"POM121","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1994,"finding":"POM121 membrane topology was established: the large C-terminal region (>90% of total mass) faces the pore side (cytoplasmic side) of the nuclear membrane, while the N-terminal portion resides in the perinuclear space, determined by differential antibody accessibility in semi-intact versus permeabilized cells.","method":"Indirect immunofluorescence with epitope-specific antibodies in semi-intact and permeabilized cells","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct topology experiment with differential permeabilization controls, single lab but two complementary conditions tested","pmids":["7525291"],"is_preprint":false},{"year":1996,"finding":"The C-terminal portion of POM121, containing the pentapeptide repeat domain, is sufficient for targeting to the nuclear envelope and for formation of intranuclear bodies when overexpressed; overexpressed POM121 accumulates in novel cylindrical intranuclear structures adjacent to the inner nuclear membrane.","method":"Immunofluorescence and fluorescence digital imaging microscopy of heterologously overexpressed POM121 deletion constructs in COS cells","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain deletion analysis with direct imaging, single lab","pmids":["8635519"],"is_preprint":false},{"year":2003,"finding":"Amino acids 1–129 of POM121 retain a GFP fusion in the ER membrane by a direct retention mechanism (not retrieval), preventing its exit to the Golgi or plasma membrane; this ER retention likely contributes to sorting of POM121 to nuclear pores.","method":"GFP-tagged deletion mutant localization, FRAP, FLIP, 15°C block experiments in live cells","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple live-imaging methods (FRAP, FLIP, temperature block) in a single lab study","pmids":["12651151"],"is_preprint":false},{"year":2004,"finding":"POM121 is specifically degraded during apoptosis by a caspase-3-dependent process; a caspase-resistant mutant of POM121-GFP resisted degradation and was detected in clustered nuclear pores even in late apoptosis, placing POM121 cleavage upstream of phosphatidylserine externalization.","method":"Live-cell imaging of POM121-GFP and caspase-resistant mutant, annexin V labeling temporal comparison","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — caspase-resistant mutant rescue plus temporal ordering with annexin V, single lab","pmids":["15258468"],"is_preprint":false},{"year":2005,"finding":"POM121, but not gp210, is essential for nuclear envelope (NE) formation in Xenopus in vitro NE assembly assays; depletion of POM121-containing membrane vesicles or the protein itself does not affect vesicle binding to chromatin but prevents membrane fusion to form a closed NE. When the Nup107-160 complex is co-depleted, POM121 becomes dispensable, revealing a functional checkpoint linking NPC assembly state to NE formation.","method":"Xenopus in vitro NE assembly assay with immunodepletion of POM121 and Nup107-160 complex, epistasis analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro assembly system, epistasis by double depletion, mechanistically defined checkpoint","pmids":["15629719"],"is_preprint":false},{"year":2006,"finding":"POM121 can recruit nucleoporins Nup62 and Nup358 to ectopic assembly sites, acting as a nucleation site for NPC substructure assembly. However, functional NPCs and intact NEs persist in severely POM121-depleted cells, and POM121/gp210 double knockdown still supports NPC assembly, indicating extensive redundancy and additional membrane-integral anchoring proteins.","method":"siRNA knockdown (single and double) in HeLa cells and human fibroblasts; ectopic NPC assembly assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal knockdown epistasis, multiple cell types, ectopic assembly assay, replicated across conditions","pmids":["16702234"],"is_preprint":false},{"year":2007,"finding":"In human HeLa cells, two distinct POM121 gene loci each produce full-length Pom121 protein; RNAi depletion of both significantly reduces the number of assembled NPCs on the nuclear envelope and induces NPC clustering, demonstrating a role in NPC maintenance and organization.","method":"RNAi depletion of both POM121 paralogs, quantitative NPC counting by immunofluorescence","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual RNAi with quantitative NPC phenotype, single lab","pmids":["17900573"],"is_preprint":false},{"year":2008,"finding":"Recruitment of membrane vesicles containing POM121 (and NDC1) to the forming nucleus is dependent on chromatin-bound ELYS/Nup107-160 complex; a direct interaction between the cytoplasmic domain of POM121 and the Nup107-160 complex was identified, placing POM121 recruitment downstream of ELYS and Nup107-160 in the NPC assembly order.","method":"Xenopus in vitro NPC assembly with immunodepletion and add-back, interaction between POM121 cytoplasmic domain and Nup107-160 complex by pulldown","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reconstituted Xenopus system plus direct protein interaction, defined assembly order","pmids":["18596237"],"is_preprint":false},{"year":2009,"finding":"Depletion of POM121 (or gp210) does not affect the NPC localization of ALADIN nucleoporin; NDC1, not POM121 or GP210, is the main anchor for ALADIN within the NPC, as shown by siRNA knockdown and FRET measurements.","method":"siRNA knockdown in stably expressing GFP-ALADIN HeLa cells; FRET measurements","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA epistasis and FRET in single lab; negative result for POM121-ALADIN anchoring is mechanistically informative","pmids":["19782045"],"is_preprint":false},{"year":2010,"finding":"Pom121 contains functional nuclear localization signals (NLS) that bind importin α/β; these NLS sites mediate interactions with a group of nucleoporins in an NLS-dependent manner. In vivo replacement of Pom121 with an NLS mutant version caused defective nuclear transport, aberrant cytoplasmic membrane stacks, and decreased cell viability.","method":"Co-immunoprecipitation, NLS mutagenesis, in vivo rescue assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — NLS mutagenesis with multiple functional readouts, single lab","pmids":["20624389"],"is_preprint":false},{"year":2011,"finding":"POM121 is present at new NPC assembly sites during interphase coinciding with inner and outer nuclear membrane fusion; overexpression of POM121 causes juxtaposition of the INM and ONM. Sun1, an INM protein, is specifically required for interphase NPC assembly and colocalizes with POM121 at forming pores, suggesting a transient POM121-Sun1 interaction promotes early interphase NPC assembly.","method":"Live-cell imaging, overexpression, siRNA knockdown of Sun1 and POM121, colocalization by fluorescence microscopy","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (OE, KD, live imaging), single lab","pmids":["21727197"],"is_preprint":false},{"year":2011,"finding":"Pom121 is indispensable for an early step in interphase NPC assembly; its NLS sequences bind importin β via importin α (RanGTP-dependent) and are essential for targeting Pom121 to interphase NPCs. A domain of Pom121 that interacts with the INM and lamin B receptor is required for NPC targeting. Pom121 localizes at the INM in the absence of a complete NPC, supporting a model where INM-seeded Pom121 initiates interphase NPC assembly.","method":"siRNA plus cell fusion-based NPC assembly assay; domain deletion and NLS mutagenesis; fractionation and colocalization","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — cell fusion assembly assay combined with domain/mutagenesis analysis and fractionation, single lab with multiple orthogonal methods","pmids":["21289085"],"is_preprint":false},{"year":2011,"finding":"A soluble internal fragment of POM121 acts as a dominant-negative inhibitor of both mitotic and interphase NPC assembly in a cell-free reconstitution system; it binds chromatin at sites distinct from ELYS-Nup107-160 seeding sites and prevents membrane enclosure. Importin-β negatively regulates chromatin binding by this POM121 fragment through a conserved NLS motif, and also affects endogenous POM121 recruitment to chromatin.","method":"Xenopus cell-free NPC assembly reconstitution, dominant-negative fragment, scanning electron microscopy, importin-β regulation assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted cell-free system with dominant-negative approach, SEM, and importin-β functional assay in one study","pmids":["22100917"],"is_preprint":false},{"year":2015,"finding":"The NLS of RnPom121 can functionally substitute for the NLS of yeast Heh2 in driving INM localization in yeast cells and rescues the subcellular localization and synthetic sickness of Heh2ΔNLS mutants; the NLS adopts a similar fold as the Heh2 NLS when transport-factor bound, confirming evolutionary conservation of active INM import.","method":"Cross-species NLS rescue experiments in yeast; structural comparison; reporter localization in HEK293T cells","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue in yeast plus reporter localization in human cells, single lab","pmids":["26179916"],"is_preprint":false},{"year":2018,"finding":"POM121 promotes nuclear import of key oncogenic transcription factors E2F1, MYC, and the androgen receptor (AR)-GATA2 complex via importin-dependent nuclear transport in prostate cancer cells; loss-of-function genetic screen identified POM121 as a key contributor to prostate cancer aggressiveness, and pharmacological inhibition of importin β decreased tumor growth and restored therapy efficacy in patient-derived models.","method":"Focused loss-of-function genetic screen, nuclear transport assays, importazole pharmacological inhibition, patient-derived xenograft models","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic screen, direct transport assays, pharmacological rescue in patient-derived preclinical models, multiple oncogenic cargoes validated","pmids":["30100187"],"is_preprint":false},{"year":2019,"finding":"POM121 inhibits NF-κB signaling in macrophages by repressing nuclear accumulation of phosphorylated P65; conditional knockout of POM121 in macrophages (POM121fl/fl Lyzm-Cre+ mice) increased susceptibility to LPS-induced acute lung injury with elevated TNF-α and IL-6.","method":"Macrophage-specific conditional knockout mouse, LPS stimulation, Western blot for phos-P65 nuclear localization, cytokine measurement","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO mouse model with mechanistic nuclear transport readout, single lab","pmids":["30802453"],"is_preprint":false},{"year":2020,"finding":"In C9orf72 ALS/FTD iPSC-derived neurons, expanded G4C2 repeat RNA reduces POM121 expression, which initiates a cascade decreasing seven additional nucleoporins, disrupts Ran GTPase localization, and leads to cellular toxicity; POM121 reduction is the initiating event in this pathological nucleoporin cascade.","method":"Super-resolution structured illumination microscopy of nucleoporins in iPSNs, siRNA-mediated reduction of POM121, quantification of 23 nucleoporins","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — super-resolution imaging plus targeted siRNA in disease-relevant iPSNs, single lab","pmids":["32673563"],"is_preprint":false},{"year":2022,"finding":"SIGMAR1 (Sigma-1 receptor) chaperones POM121 at the nuclear pore, facilitating KPNB1/importin-β1 recruitment and thereby enabling TFEB nuclear transport for autophagy induction; in C9orf72 ALS-FTD cells, HRE disrupts the SIGMAR1-POM121 interaction, reducing nuclear TFEB, KPNB1, and LC3-II; overexpression of SIGMAR1, POM121, or SIGMAR1 agonist pridopidine rescues these deficits.","method":"Co-immunoprecipitation, overexpression, siRNA, pharmacological activation (pridopidine), Western blot for nuclear TFEB/KPNB1/LC3-II","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of SIGMAR1-POM121 interaction, multiple rescue approaches, single lab","pmids":["35507432"],"is_preprint":false},{"year":2024,"finding":"A peptide region downstream of the NLS of POM121 acts as a cytoplasmic interactor of PPARγ; CRISPR/Cas9 or siRNA silencing of POM121A/C enforces nuclear accumulation of PPARγ and activates PPARγ target genes promoting lipid metabolism and cell cycle arrest, reducing CRC cell proliferation.","method":"CRISPR/Cas9 and siRNA silencing, nuclear fractionation, PPARγ target gene expression analysis, peptide interaction mapping","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR and siRNA with defined nuclear localization readout and downstream gene expression, single lab","pmids":["38177114"],"is_preprint":false},{"year":2024,"finding":"In C9orf72 ALS iPSC-derived neurons, POM121 shifts from the nuclear ring to the inner ring position within the NPC as visualized by pan-Expansion Microscopy, indicating a structural repositioning of POM121 within the NPC architecture under pathological conditions.","method":"pan-Expansion Microscopy with machine-learning segmentation of NPC sub-rings","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single imaging method in a preprint, no functional follow-up of POM121 repositioning","pmids":[],"is_preprint":true},{"year":2025,"finding":"Poly-PR dipeptide repeat protein reduces Pom121 expression in motor neurons (NSC-34 cells and AAV-poly-PR42 mouse model), causing cytoplasmic mislocalization of ATF3 transcription factor and nuclear envelope damage; Pom121 overexpression restores nuclear ATF3 localization and alleviates poly-PR toxicity. Sigma-1R stabilizes Pom121 under oxidative stress, defining a Sigma-1R/Pom121/ATF3 protective axis.","method":"siRNA/overexpression in NSC-34 cells, AAV mouse model, nuclear fractionation, immunofluorescence for ATF3 localization, cell viability assays","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo AAV mouse model plus cellular rescue experiments, single lab, multiple readouts","pmids":["40480424"],"is_preprint":false},{"year":2026,"finding":"O-GlcNAcylation of POM121 at Ser199 (by OGT) attenuates its interaction with E3 ubiquitin ligase TRIM21, thereby preventing ubiquitination and stabilizing POM121 protein; accumulated POM121 then enhances nuclear import of c-MYC, which transcriptionally activates ECM-related genes driving NSCLC bone metastasis.","method":"Mass spectrometry identification of O-GlcNAcylation site, mutagenesis (Ser199), Co-IP of POM121-TRIM21 interaction, ubiquitination assay, nuclear import assay for c-MYC","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific PTM identified by MS with mutagenesis, Co-IP of E3 ligase interaction, nuclear import functional readout, single lab","pmids":["41629644"],"is_preprint":false},{"year":2026,"finding":"H3K18 lactylation enrichment at the POM121 promoter region drives enhanced POM121 transcription in gastric cancer, as demonstrated by ChIP and dual-luciferase reporter assays; reduced H3K18la (via LDHA/LDHB silencing) decreases POM121 expression and suppresses tumor progression, which is rescued by POM121 overexpression.","method":"ChIP assay, dual-luciferase reporter assay, LDHA/LDHB siRNA, POM121 overexpression rescue","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus luciferase reporter assay and rescue experiment, single lab","pmids":["41864048"],"is_preprint":false}],"current_model":"POM121 is an integral transmembrane nucleoporin that anchors within the nuclear envelope pore membrane with its large C-terminal domain facing the NPC lumen; it acts as a nucleation site for NPC assembly by interacting with the Nup107-160 complex downstream of ELYS recruitment to AT-rich chromatin, is essential for nuclear membrane fusion during post-mitotic NE reformation, drives interphase NPC assembly via importin α/β-dependent targeting of its NLS to the inner nuclear membrane, and regulates nuclear import of oncogenic transcription factors (E2F1, MYC, AR, PPARγ, ATF3, TFEB) through importin-β—a function modulated by SIGMAR1 chaperoning, O-GlcNAcylation-dependent stabilization via TRIM21 antagonism, and H3K18 lactylation-driven transcriptional upregulation."},"narrative":{"mechanistic_narrative":"POM121 is an integral membrane nucleoporin that functions both as a structural seed for nuclear pore complex (NPC) assembly and as a selective regulator of nuclear protein import [PMID:16702234, PMID:30100187]. Its membrane topology orients the bulk C-terminal mass toward the pore side of the nuclear membrane while the N-terminus resides in the perinuclear space, and an N-terminal segment directs ER membrane retention that contributes to sorting toward nuclear pores [PMID:7525291, PMID:12651151]. During post-mitotic NE reformation in reconstituted Xenopus systems, POM121 is dispensable for membrane vesicle binding to chromatin but essential for the membrane fusion that closes the NE; this requirement is gated by the Nup107-160 complex, whose co-depletion makes POM121 unnecessary, defining a checkpoint linking NPC assembly state to NE closure [PMID:15629719]. POM121 is recruited downstream of chromatin-bound ELYS and the Nup107-160 complex through a direct interaction between its cytoplasmic domain and Nup107-160, and it can nucleate substructure assembly by recruiting nucleoporins such as Nup62 and Nup358 to ectopic sites [PMID:16702234, PMID:18596237]. In interphase, POM121 seeds new NPCs from the inner nuclear membrane: its NLS sequences bind importin α/β in a RanGTP-dependent manner to target the protein to the INM, where it engages the INM and lamin B receptor and transiently associates with Sun1 to initiate de novo assembly; importin-β reciprocally limits POM121 chromatin binding [PMID:21289085, PMID:21727197, PMID:22100917]. Beyond architecture, POM121 acts as a rate-limiting determinant of importin-β-dependent nuclear import for a range of transcription factors, promoting nuclear entry of E2F1, MYC, and the AR-GATA2 complex to drive prostate cancer aggressiveness, restraining NF-κB p65 and PPARγ nuclear accumulation, and supporting TFEB and ATF3 import [PMID:30100187, PMID:30802453, PMID:38177114, PMID:35507432, PMID:40480424]. This import gateway is modulated by SIGMAR1 chaperoning that facilitates KPNB1 recruitment, by O-GlcNAcylation at Ser199 that antagonizes TRIM21-mediated ubiquitination to stabilize POM121, and by H3K18-lactylation-driven transcriptional upregulation [PMID:35507432, PMID:41629644, PMID:41864048]. Loss of POM121 is the initiating event in a nucleoporin cascade and nucleocytoplasmic transport collapse in C9orf72 ALS/FTD neurons [PMID:32673563].","teleology":[{"year":1994,"claim":"Established the membrane topology of POM121, defining how this transmembrane nucleoporin is oriented within the pore membrane — a prerequisite for understanding its anchoring and interaction surfaces.","evidence":"Differential antibody accessibility in semi-intact versus permeabilized cells","pmids":["7525291"],"confidence":"Medium","gaps":["No high-resolution structural model of the membrane-spanning region","Functional contribution of the perinuclear N-terminus not defined"]},{"year":2003,"claim":"Identified an N-terminal ER membrane retention determinant, showing how POM121 is sorted away from the secretory pathway toward nuclear pores.","evidence":"GFP-tagged deletion mutants with FRAP, FLIP, and 15°C block in live cells","pmids":["12651151"],"confidence":"Medium","gaps":["Molecular mechanism of retention not identified","Link between ER retention and INM targeting not directly demonstrated"]},{"year":2005,"claim":"Demonstrated that POM121 is essential for NE membrane fusion during assembly and revealed a checkpoint coupling its requirement to Nup107-160, establishing the order between NPC assembly and NE closure.","evidence":"Xenopus in vitro NE assembly with immunodepletion and double-depletion epistasis","pmids":["15629719"],"confidence":"High","gaps":["Molecular basis of the membrane fusion step not defined","How Nup107-160 status bypasses POM121 requirement unresolved"]},{"year":2006,"claim":"Showed POM121 can nucleate NPC substructure assembly by recruiting Nup62 and Nup358, while also revealing functional redundancy since NPCs persist after depletion.","evidence":"Single and double siRNA knockdown and ectopic NPC assembly assay in HeLa and fibroblasts","pmids":["16702234"],"confidence":"High","gaps":["Identity of redundant membrane-integral anchors not determined","Direct binding interfaces for Nup62/Nup358 recruitment not mapped"]},{"year":2008,"claim":"Placed POM121 recruitment downstream of ELYS/Nup107-160 in the assembly hierarchy via a direct cytoplasmic-domain interaction, ordering the early steps of NPC formation.","evidence":"Xenopus in vitro assembly with immunodepletion/add-back and pulldown of POM121 cytoplasmic domain with Nup107-160","pmids":["18596237"],"confidence":"High","gaps":["Stoichiometry and affinity of the POM121–Nup107-160 interaction not quantified","Structural details of the interaction interface unknown"]},{"year":2009,"claim":"Distinguished POM121 from NDC1 by showing POM121 is not the anchor for ALADIN, refining the division of labor among transmembrane nucleoporins.","evidence":"siRNA knockdown and FRET in GFP-ALADIN HeLa cells","pmids":["19782045"],"confidence":"Medium","gaps":["Full set of POM121-anchored nucleoporins not defined"]},{"year":2011,"claim":"Defined an importin α/β-dependent NLS mechanism that targets POM121 to the inner nuclear membrane to seed interphase NPC assembly, with INM/lamin B receptor and Sun1 contributions, establishing a distinct de novo assembly pathway.","evidence":"Cell-fusion NPC assembly assay, NLS/domain mutagenesis, fractionation, and Sun1 co-localization/knockdown","pmids":["21289085","21727197"],"confidence":"High","gaps":["Transience and direct nature of POM121–Sun1 interaction not biochemically confirmed","How RanGTP gradient spatially restricts INM targeting unresolved"]},{"year":2011,"claim":"Showed importin-β negatively regulates POM121 chromatin binding through its NLS, providing a regulatory logic for spatial control of assembly seeding.","evidence":"Xenopus cell-free assembly with dominant-negative POM121 fragment, SEM, and importin-β assay","pmids":["22100917"],"confidence":"High","gaps":["Endogenous chromatin binding sites of POM121 not molecularly defined","Relationship between this chromatin binding and ELYS seeding sites unclear"]},{"year":2015,"claim":"Demonstrated evolutionary conservation of POM121's active INM-import NLS by functional substitution for the yeast Heh2 NLS, supporting a conserved transport-factor-mediated INM targeting mechanism.","evidence":"Cross-species NLS rescue in yeast and reporter localization in HEK293T cells","pmids":["26179916"],"confidence":"Medium","gaps":["Structural model based on comparison, not direct POM121 structure"]},{"year":2018,"claim":"Reframed POM121 as a rate-limiting importin-β-dependent gateway for nuclear import of oncogenic transcription factors (E2F1, MYC, AR-GATA2), linking nuclear transport capacity to cancer aggressiveness.","evidence":"Loss-of-function genetic screen, nuclear transport assays, importazole inhibition, patient-derived xenografts","pmids":["30100187"],"confidence":"High","gaps":["Whether cargo selectivity is direct or via altered NPC composition not resolved","Mechanism distinguishing oncogenic cargoes from bulk import unknown"]},{"year":2019,"claim":"Extended POM121's import-regulatory role to immune signaling, showing it restrains nuclear accumulation of phospho-p65 to dampen NF-κB-driven inflammation.","evidence":"Macrophage-specific conditional knockout mice, LPS challenge, phospho-p65 Western blot, cytokine measurement","pmids":["30802453"],"confidence":"Medium","gaps":["Direct interaction of POM121 with p65 import machinery not shown","How POM121 selectively limits p65 import unclear"]},{"year":2020,"claim":"Identified POM121 loss as the initiating event in a nucleoporin-depletion cascade and Ran disruption in C9orf72 ALS/FTD neurons, positioning it at the apex of nucleocytoplasmic transport failure.","evidence":"Super-resolution SIM of nucleoporins and siRNA in iPSC-derived neurons","pmids":["32673563"],"confidence":"Medium","gaps":["Mechanism by which G4C2 RNA reduces POM121 not defined","Causal chain from POM121 loss to downstream Nup decrease not fully resolved"]},{"year":2022,"claim":"Defined SIGMAR1 as a chaperone that supports POM121-dependent KPNB1 recruitment to enable TFEB nuclear import and autophagy, with disruption in C9orf72 disease.","evidence":"Co-IP, overexpression/siRNA, pridopidine activation, nuclear TFEB/KPNB1/LC3-II Western blots","pmids":["35507432"],"confidence":"Medium","gaps":["Direct biochemical nature of SIGMAR1-POM121 chaperoning not structurally defined","Single-lab Co-IP without reciprocal structural validation"]},{"year":2024,"claim":"Showed POM121 cytoplasmically sequesters PPARγ via a region downstream of its NLS, so that POM121 loss enforces PPARγ nuclear accumulation and growth arrest in colorectal cancer.","evidence":"CRISPR/Cas9 and siRNA silencing, nuclear fractionation, target gene expression, peptide interaction mapping","pmids":["38177114"],"confidence":"Medium","gaps":["Direct binding affinity and structure of POM121-PPARγ interaction not determined","Generality of cytoplasmic sequestration versus import gating unresolved"]},{"year":2024,"claim":"Reported a pathological structural repositioning of POM121 from the nuclear ring to the inner ring in C9orf72 ALS neurons, hinting at architectural remodeling of the NPC under disease.","evidence":"pan-Expansion Microscopy with machine-learning NPC sub-ring segmentation (preprint)","pmids":[],"confidence":"Low","gaps":["Single imaging method in a preprint with no functional follow-up","Functional consequence of repositioning unknown"]},{"year":2025,"claim":"Defined a Sigma-1R/POM121/ATF3 protective axis in which poly-PR-induced POM121 loss mislocalizes ATF3 and damages the NE, while POM121 restoration rescues toxicity.","evidence":"siRNA/overexpression in NSC-34 cells, AAV-poly-PR mouse model, nuclear fractionation, ATF3 immunofluorescence, viability assays","pmids":["40480424"],"confidence":"Medium","gaps":["Mechanism of Sigma-1R-mediated POM121 stabilization under oxidative stress not biochemically defined","Whether ATF3 mislocalization is direct POM121-dependent import not shown"]},{"year":2026,"claim":"Established post-translational and transcriptional control of POM121 abundance: O-GlcNAcylation at Ser199 blocks TRIM21-mediated degradation, and H3K18 lactylation upregulates transcription, both increasing POM121-driven oncogenic import.","evidence":"MS site mapping with Ser199 mutagenesis, POM121-TRIM21 Co-IP and ubiquitination assays, c-MYC import assays; ChIP and dual-luciferase reporter with LDHA/LDHB silencing and rescue","pmids":["41629644","41864048"],"confidence":"Medium","gaps":["Whether OGT and lactylation pathways converge on the same POM121 pool not addressed","Structural impact of Ser199 modification on TRIM21 binding not resolved"]},{"year":null,"claim":"How POM121 achieves cargo selectivity — distinguishing specific oncogenic and signaling transcription factors from bulk nuclear import — and how its dual roles in NPC architecture versus selective import are mechanistically separated remain open.","evidence":"No direct experimental resolution in the available corpus","pmids":[],"confidence":"Low","gaps":["No structure of POM121 cargo-discriminating interfaces","Relationship between altered NPC composition and import selectivity unresolved","Whether disease-associated import defects reflect loss of structural seeding or loss of import gating not separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4,5,7]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[11,12,14]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[14,15,18]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,4,11]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[11,14,18]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[4,5,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[14,16,21]}],"complexes":["Nuclear pore complex (NPC)"],"partners":["NUP107","NUP62","NUP358","SUN1","KPNB1","SIGMAR1","TRIM21"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96HA1","full_name":"Nuclear envelope pore membrane protein POM 121","aliases":["Nuclear envelope pore membrane protein POM 121A","Nucleoporin Nup121","Pore membrane protein of 121 kDa"],"length_aa":1249,"mass_kda":127.7,"function":"Essential component of the nuclear pore complex (NPC). The repeat-containing domain may be involved in anchoring components of the pore complex to the pore membrane. When overexpressed in cells induces the formation of cytoplasmic annulate lamellae (AL)","subcellular_location":"Nucleus, nuclear pore complex; Nucleus membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q96HA1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/POM121","classification":"Not Classified","n_dependent_lines":66,"n_total_lines":1165,"dependency_fraction":0.05665236051502146},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"KPNA2","stoichiometry":0.2},{"gene":"KPNA3","stoichiometry":0.2},{"gene":"KPNA4","stoichiometry":0.2},{"gene":"KPNB1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/POM121","total_profiled":1310},"omim":[{"mim_id":"618353","title":"OOCYTE/ZYGOTE/EMBRYO MATURATION ARREST 6; OZEMA6","url":"https://www.omim.org/entry/618353"},{"mim_id":"615754","title":"POM121 TRANSMEMBRANE NUCLEOPORIN C; POM121C","url":"https://www.omim.org/entry/615754"},{"mim_id":"615753","title":"POM121 TRANSMEMBRANE NUCLEOPORIN; POM121","url":"https://www.omim.org/entry/615753"},{"mim_id":"611864","title":"ARMADILLO REPEAT-CONTAINING 10; ARMC10","url":"https://www.omim.org/entry/611864"},{"mim_id":"607614","title":"NUCLEOPORIN, 160-KD; NUP160","url":"https://www.omim.org/entry/607614"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Nuclear membrane","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/POM121"},"hgnc":{"alias_symbol":["KIAA0618","DKFZP586G1822","DKFZP586P2220","POM121A"],"prev_symbol":[]},"alphafold":{"accession":"Q96HA1","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96HA1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96HA1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96HA1-F1-predicted_aligned_error_v6.png","plddt_mean":42.28},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=POM121","jax_strain_url":"https://www.jax.org/strain/search?query=POM121"},"sequence":{"accession":"Q96HA1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96HA1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96HA1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96HA1"}},"corpus_meta":[{"pmid":"30100187","id":"PMC_30100187","title":"Nuclear Pores Promote Lethal Prostate Cancer by Increasing POM121-Driven E2F1, MYC, and AR 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Microscopy","date":"2024-09-20","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.18.613744","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18036,"output_tokens":5535,"usd":0.068567,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14169,"output_tokens":5463,"usd":0.10371,"stage2_stop_reason":"end_turn"},"total_usd":0.172277,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"POM121 membrane topology was established: the large C-terminal region (>90% of total mass) faces the pore side (cytoplasmic side) of the nuclear membrane, while the N-terminal portion resides in the perinuclear space, determined by differential antibody accessibility in semi-intact versus permeabilized cells.\",\n      \"method\": \"Indirect immunofluorescence with epitope-specific antibodies in semi-intact and permeabilized cells\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct topology experiment with differential permeabilization controls, single lab but two complementary conditions tested\",\n      \"pmids\": [\"7525291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The C-terminal portion of POM121, containing the pentapeptide repeat domain, is sufficient for targeting to the nuclear envelope and for formation of intranuclear bodies when overexpressed; overexpressed POM121 accumulates in novel cylindrical intranuclear structures adjacent to the inner nuclear membrane.\",\n      \"method\": \"Immunofluorescence and fluorescence digital imaging microscopy of heterologously overexpressed POM121 deletion constructs in COS cells\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain deletion analysis with direct imaging, single lab\",\n      \"pmids\": [\"8635519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Amino acids 1–129 of POM121 retain a GFP fusion in the ER membrane by a direct retention mechanism (not retrieval), preventing its exit to the Golgi or plasma membrane; this ER retention likely contributes to sorting of POM121 to nuclear pores.\",\n      \"method\": \"GFP-tagged deletion mutant localization, FRAP, FLIP, 15°C block experiments in live cells\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple live-imaging methods (FRAP, FLIP, temperature block) in a single lab study\",\n      \"pmids\": [\"12651151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"POM121 is specifically degraded during apoptosis by a caspase-3-dependent process; a caspase-resistant mutant of POM121-GFP resisted degradation and was detected in clustered nuclear pores even in late apoptosis, placing POM121 cleavage upstream of phosphatidylserine externalization.\",\n      \"method\": \"Live-cell imaging of POM121-GFP and caspase-resistant mutant, annexin V labeling temporal comparison\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — caspase-resistant mutant rescue plus temporal ordering with annexin V, single lab\",\n      \"pmids\": [\"15258468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"POM121, but not gp210, is essential for nuclear envelope (NE) formation in Xenopus in vitro NE assembly assays; depletion of POM121-containing membrane vesicles or the protein itself does not affect vesicle binding to chromatin but prevents membrane fusion to form a closed NE. When the Nup107-160 complex is co-depleted, POM121 becomes dispensable, revealing a functional checkpoint linking NPC assembly state to NE formation.\",\n      \"method\": \"Xenopus in vitro NE assembly assay with immunodepletion of POM121 and Nup107-160 complex, epistasis analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro assembly system, epistasis by double depletion, mechanistically defined checkpoint\",\n      \"pmids\": [\"15629719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"POM121 can recruit nucleoporins Nup62 and Nup358 to ectopic assembly sites, acting as a nucleation site for NPC substructure assembly. However, functional NPCs and intact NEs persist in severely POM121-depleted cells, and POM121/gp210 double knockdown still supports NPC assembly, indicating extensive redundancy and additional membrane-integral anchoring proteins.\",\n      \"method\": \"siRNA knockdown (single and double) in HeLa cells and human fibroblasts; ectopic NPC assembly assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal knockdown epistasis, multiple cell types, ectopic assembly assay, replicated across conditions\",\n      \"pmids\": [\"16702234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In human HeLa cells, two distinct POM121 gene loci each produce full-length Pom121 protein; RNAi depletion of both significantly reduces the number of assembled NPCs on the nuclear envelope and induces NPC clustering, demonstrating a role in NPC maintenance and organization.\",\n      \"method\": \"RNAi depletion of both POM121 paralogs, quantitative NPC counting by immunofluorescence\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual RNAi with quantitative NPC phenotype, single lab\",\n      \"pmids\": [\"17900573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Recruitment of membrane vesicles containing POM121 (and NDC1) to the forming nucleus is dependent on chromatin-bound ELYS/Nup107-160 complex; a direct interaction between the cytoplasmic domain of POM121 and the Nup107-160 complex was identified, placing POM121 recruitment downstream of ELYS and Nup107-160 in the NPC assembly order.\",\n      \"method\": \"Xenopus in vitro NPC assembly with immunodepletion and add-back, interaction between POM121 cytoplasmic domain and Nup107-160 complex by pulldown\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reconstituted Xenopus system plus direct protein interaction, defined assembly order\",\n      \"pmids\": [\"18596237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Depletion of POM121 (or gp210) does not affect the NPC localization of ALADIN nucleoporin; NDC1, not POM121 or GP210, is the main anchor for ALADIN within the NPC, as shown by siRNA knockdown and FRET measurements.\",\n      \"method\": \"siRNA knockdown in stably expressing GFP-ALADIN HeLa cells; FRET measurements\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA epistasis and FRET in single lab; negative result for POM121-ALADIN anchoring is mechanistically informative\",\n      \"pmids\": [\"19782045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Pom121 contains functional nuclear localization signals (NLS) that bind importin α/β; these NLS sites mediate interactions with a group of nucleoporins in an NLS-dependent manner. In vivo replacement of Pom121 with an NLS mutant version caused defective nuclear transport, aberrant cytoplasmic membrane stacks, and decreased cell viability.\",\n      \"method\": \"Co-immunoprecipitation, NLS mutagenesis, in vivo rescue assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — NLS mutagenesis with multiple functional readouts, single lab\",\n      \"pmids\": [\"20624389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"POM121 is present at new NPC assembly sites during interphase coinciding with inner and outer nuclear membrane fusion; overexpression of POM121 causes juxtaposition of the INM and ONM. Sun1, an INM protein, is specifically required for interphase NPC assembly and colocalizes with POM121 at forming pores, suggesting a transient POM121-Sun1 interaction promotes early interphase NPC assembly.\",\n      \"method\": \"Live-cell imaging, overexpression, siRNA knockdown of Sun1 and POM121, colocalization by fluorescence microscopy\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (OE, KD, live imaging), single lab\",\n      \"pmids\": [\"21727197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Pom121 is indispensable for an early step in interphase NPC assembly; its NLS sequences bind importin β via importin α (RanGTP-dependent) and are essential for targeting Pom121 to interphase NPCs. A domain of Pom121 that interacts with the INM and lamin B receptor is required for NPC targeting. Pom121 localizes at the INM in the absence of a complete NPC, supporting a model where INM-seeded Pom121 initiates interphase NPC assembly.\",\n      \"method\": \"siRNA plus cell fusion-based NPC assembly assay; domain deletion and NLS mutagenesis; fractionation and colocalization\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — cell fusion assembly assay combined with domain/mutagenesis analysis and fractionation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21289085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A soluble internal fragment of POM121 acts as a dominant-negative inhibitor of both mitotic and interphase NPC assembly in a cell-free reconstitution system; it binds chromatin at sites distinct from ELYS-Nup107-160 seeding sites and prevents membrane enclosure. Importin-β negatively regulates chromatin binding by this POM121 fragment through a conserved NLS motif, and also affects endogenous POM121 recruitment to chromatin.\",\n      \"method\": \"Xenopus cell-free NPC assembly reconstitution, dominant-negative fragment, scanning electron microscopy, importin-β regulation assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted cell-free system with dominant-negative approach, SEM, and importin-β functional assay in one study\",\n      \"pmids\": [\"22100917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The NLS of RnPom121 can functionally substitute for the NLS of yeast Heh2 in driving INM localization in yeast cells and rescues the subcellular localization and synthetic sickness of Heh2ΔNLS mutants; the NLS adopts a similar fold as the Heh2 NLS when transport-factor bound, confirming evolutionary conservation of active INM import.\",\n      \"method\": \"Cross-species NLS rescue experiments in yeast; structural comparison; reporter localization in HEK293T cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue in yeast plus reporter localization in human cells, single lab\",\n      \"pmids\": [\"26179916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"POM121 promotes nuclear import of key oncogenic transcription factors E2F1, MYC, and the androgen receptor (AR)-GATA2 complex via importin-dependent nuclear transport in prostate cancer cells; loss-of-function genetic screen identified POM121 as a key contributor to prostate cancer aggressiveness, and pharmacological inhibition of importin β decreased tumor growth and restored therapy efficacy in patient-derived models.\",\n      \"method\": \"Focused loss-of-function genetic screen, nuclear transport assays, importazole pharmacological inhibition, patient-derived xenograft models\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic screen, direct transport assays, pharmacological rescue in patient-derived preclinical models, multiple oncogenic cargoes validated\",\n      \"pmids\": [\"30100187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"POM121 inhibits NF-κB signaling in macrophages by repressing nuclear accumulation of phosphorylated P65; conditional knockout of POM121 in macrophages (POM121fl/fl Lyzm-Cre+ mice) increased susceptibility to LPS-induced acute lung injury with elevated TNF-α and IL-6.\",\n      \"method\": \"Macrophage-specific conditional knockout mouse, LPS stimulation, Western blot for phos-P65 nuclear localization, cytokine measurement\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mouse model with mechanistic nuclear transport readout, single lab\",\n      \"pmids\": [\"30802453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In C9orf72 ALS/FTD iPSC-derived neurons, expanded G4C2 repeat RNA reduces POM121 expression, which initiates a cascade decreasing seven additional nucleoporins, disrupts Ran GTPase localization, and leads to cellular toxicity; POM121 reduction is the initiating event in this pathological nucleoporin cascade.\",\n      \"method\": \"Super-resolution structured illumination microscopy of nucleoporins in iPSNs, siRNA-mediated reduction of POM121, quantification of 23 nucleoporins\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — super-resolution imaging plus targeted siRNA in disease-relevant iPSNs, single lab\",\n      \"pmids\": [\"32673563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIGMAR1 (Sigma-1 receptor) chaperones POM121 at the nuclear pore, facilitating KPNB1/importin-β1 recruitment and thereby enabling TFEB nuclear transport for autophagy induction; in C9orf72 ALS-FTD cells, HRE disrupts the SIGMAR1-POM121 interaction, reducing nuclear TFEB, KPNB1, and LC3-II; overexpression of SIGMAR1, POM121, or SIGMAR1 agonist pridopidine rescues these deficits.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, siRNA, pharmacological activation (pridopidine), Western blot for nuclear TFEB/KPNB1/LC3-II\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of SIGMAR1-POM121 interaction, multiple rescue approaches, single lab\",\n      \"pmids\": [\"35507432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A peptide region downstream of the NLS of POM121 acts as a cytoplasmic interactor of PPARγ; CRISPR/Cas9 or siRNA silencing of POM121A/C enforces nuclear accumulation of PPARγ and activates PPARγ target genes promoting lipid metabolism and cell cycle arrest, reducing CRC cell proliferation.\",\n      \"method\": \"CRISPR/Cas9 and siRNA silencing, nuclear fractionation, PPARγ target gene expression analysis, peptide interaction mapping\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR and siRNA with defined nuclear localization readout and downstream gene expression, single lab\",\n      \"pmids\": [\"38177114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In C9orf72 ALS iPSC-derived neurons, POM121 shifts from the nuclear ring to the inner ring position within the NPC as visualized by pan-Expansion Microscopy, indicating a structural repositioning of POM121 within the NPC architecture under pathological conditions.\",\n      \"method\": \"pan-Expansion Microscopy with machine-learning segmentation of NPC sub-rings\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single imaging method in a preprint, no functional follow-up of POM121 repositioning\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Poly-PR dipeptide repeat protein reduces Pom121 expression in motor neurons (NSC-34 cells and AAV-poly-PR42 mouse model), causing cytoplasmic mislocalization of ATF3 transcription factor and nuclear envelope damage; Pom121 overexpression restores nuclear ATF3 localization and alleviates poly-PR toxicity. Sigma-1R stabilizes Pom121 under oxidative stress, defining a Sigma-1R/Pom121/ATF3 protective axis.\",\n      \"method\": \"siRNA/overexpression in NSC-34 cells, AAV mouse model, nuclear fractionation, immunofluorescence for ATF3 localization, cell viability assays\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo AAV mouse model plus cellular rescue experiments, single lab, multiple readouts\",\n      \"pmids\": [\"40480424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"O-GlcNAcylation of POM121 at Ser199 (by OGT) attenuates its interaction with E3 ubiquitin ligase TRIM21, thereby preventing ubiquitination and stabilizing POM121 protein; accumulated POM121 then enhances nuclear import of c-MYC, which transcriptionally activates ECM-related genes driving NSCLC bone metastasis.\",\n      \"method\": \"Mass spectrometry identification of O-GlcNAcylation site, mutagenesis (Ser199), Co-IP of POM121-TRIM21 interaction, ubiquitination assay, nuclear import assay for c-MYC\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific PTM identified by MS with mutagenesis, Co-IP of E3 ligase interaction, nuclear import functional readout, single lab\",\n      \"pmids\": [\"41629644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"H3K18 lactylation enrichment at the POM121 promoter region drives enhanced POM121 transcription in gastric cancer, as demonstrated by ChIP and dual-luciferase reporter assays; reduced H3K18la (via LDHA/LDHB silencing) decreases POM121 expression and suppresses tumor progression, which is rescued by POM121 overexpression.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter assay, LDHA/LDHB siRNA, POM121 overexpression rescue\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus luciferase reporter assay and rescue experiment, single lab\",\n      \"pmids\": [\"41864048\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"POM121 is an integral transmembrane nucleoporin that anchors within the nuclear envelope pore membrane with its large C-terminal domain facing the NPC lumen; it acts as a nucleation site for NPC assembly by interacting with the Nup107-160 complex downstream of ELYS recruitment to AT-rich chromatin, is essential for nuclear membrane fusion during post-mitotic NE reformation, drives interphase NPC assembly via importin α/β-dependent targeting of its NLS to the inner nuclear membrane, and regulates nuclear import of oncogenic transcription factors (E2F1, MYC, AR, PPARγ, ATF3, TFEB) through importin-β—a function modulated by SIGMAR1 chaperoning, O-GlcNAcylation-dependent stabilization via TRIM21 antagonism, and H3K18 lactylation-driven transcriptional upregulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"POM121 is an integral membrane nucleoporin that functions both as a structural seed for nuclear pore complex (NPC) assembly and as a selective regulator of nuclear protein import [#5, #14]. Its membrane topology orients the bulk C-terminal mass toward the pore side of the nuclear membrane while the N-terminus resides in the perinuclear space, and an N-terminal segment directs ER membrane retention that contributes to sorting toward nuclear pores [#0, #2]. During post-mitotic NE reformation in reconstituted Xenopus systems, POM121 is dispensable for membrane vesicle binding to chromatin but essential for the membrane fusion that closes the NE; this requirement is gated by the Nup107-160 complex, whose co-depletion makes POM121 unnecessary, defining a checkpoint linking NPC assembly state to NE closure [#4]. POM121 is recruited downstream of chromatin-bound ELYS and the Nup107-160 complex through a direct interaction between its cytoplasmic domain and Nup107-160, and it can nucleate substructure assembly by recruiting nucleoporins such as Nup62 and Nup358 to ectopic sites [#5, #7]. In interphase, POM121 seeds new NPCs from the inner nuclear membrane: its NLS sequences bind importin α/β in a RanGTP-dependent manner to target the protein to the INM, where it engages the INM and lamin B receptor and transiently associates with Sun1 to initiate de novo assembly; importin-β reciprocally limits POM121 chromatin binding [#11, #10, #12]. Beyond architecture, POM121 acts as a rate-limiting determinant of importin-β-dependent nuclear import for a range of transcription factors, promoting nuclear entry of E2F1, MYC, and the AR-GATA2 complex to drive prostate cancer aggressiveness, restraining NF-κB p65 and PPARγ nuclear accumulation, and supporting TFEB and ATF3 import [#14, #15, #18, #17, #20]. This import gateway is modulated by SIGMAR1 chaperoning that facilitates KPNB1 recruitment, by O-GlcNAcylation at Ser199 that antagonizes TRIM21-mediated ubiquitination to stabilize POM121, and by H3K18-lactylation-driven transcriptional upregulation [#17, #21, #22]. Loss of POM121 is the initiating event in a nucleoporin cascade and nucleocytoplasmic transport collapse in C9orf72 ALS/FTD neurons [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established the membrane topology of POM121, defining how this transmembrane nucleoporin is oriented within the pore membrane — a prerequisite for understanding its anchoring and interaction surfaces.\",\n      \"evidence\": \"Differential antibody accessibility in semi-intact versus permeabilized cells\",\n      \"pmids\": [\"7525291\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structural model of the membrane-spanning region\", \"Functional contribution of the perinuclear N-terminus not defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified an N-terminal ER membrane retention determinant, showing how POM121 is sorted away from the secretory pathway toward nuclear pores.\",\n      \"evidence\": \"GFP-tagged deletion mutants with FRAP, FLIP, and 15°C block in live cells\",\n      \"pmids\": [\"12651151\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of retention not identified\", \"Link between ER retention and INM targeting not directly demonstrated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated that POM121 is essential for NE membrane fusion during assembly and revealed a checkpoint coupling its requirement to Nup107-160, establishing the order between NPC assembly and NE closure.\",\n      \"evidence\": \"Xenopus in vitro NE assembly with immunodepletion and double-depletion epistasis\",\n      \"pmids\": [\"15629719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the membrane fusion step not defined\", \"How Nup107-160 status bypasses POM121 requirement unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed POM121 can nucleate NPC substructure assembly by recruiting Nup62 and Nup358, while also revealing functional redundancy since NPCs persist after depletion.\",\n      \"evidence\": \"Single and double siRNA knockdown and ectopic NPC assembly assay in HeLa and fibroblasts\",\n      \"pmids\": [\"16702234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of redundant membrane-integral anchors not determined\", \"Direct binding interfaces for Nup62/Nup358 recruitment not mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Placed POM121 recruitment downstream of ELYS/Nup107-160 in the assembly hierarchy via a direct cytoplasmic-domain interaction, ordering the early steps of NPC formation.\",\n      \"evidence\": \"Xenopus in vitro assembly with immunodepletion/add-back and pulldown of POM121 cytoplasmic domain with Nup107-160\",\n      \"pmids\": [\"18596237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and affinity of the POM121–Nup107-160 interaction not quantified\", \"Structural details of the interaction interface unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Distinguished POM121 from NDC1 by showing POM121 is not the anchor for ALADIN, refining the division of labor among transmembrane nucleoporins.\",\n      \"evidence\": \"siRNA knockdown and FRET in GFP-ALADIN HeLa cells\",\n      \"pmids\": [\"19782045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Full set of POM121-anchored nucleoporins not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined an importin α/β-dependent NLS mechanism that targets POM121 to the inner nuclear membrane to seed interphase NPC assembly, with INM/lamin B receptor and Sun1 contributions, establishing a distinct de novo assembly pathway.\",\n      \"evidence\": \"Cell-fusion NPC assembly assay, NLS/domain mutagenesis, fractionation, and Sun1 co-localization/knockdown\",\n      \"pmids\": [\"21289085\", \"21727197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transience and direct nature of POM121–Sun1 interaction not biochemically confirmed\", \"How RanGTP gradient spatially restricts INM targeting unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed importin-β negatively regulates POM121 chromatin binding through its NLS, providing a regulatory logic for spatial control of assembly seeding.\",\n      \"evidence\": \"Xenopus cell-free assembly with dominant-negative POM121 fragment, SEM, and importin-β assay\",\n      \"pmids\": [\"22100917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous chromatin binding sites of POM121 not molecularly defined\", \"Relationship between this chromatin binding and ELYS seeding sites unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated evolutionary conservation of POM121's active INM-import NLS by functional substitution for the yeast Heh2 NLS, supporting a conserved transport-factor-mediated INM targeting mechanism.\",\n      \"evidence\": \"Cross-species NLS rescue in yeast and reporter localization in HEK293T cells\",\n      \"pmids\": [\"26179916\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural model based on comparison, not direct POM121 structure\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Reframed POM121 as a rate-limiting importin-β-dependent gateway for nuclear import of oncogenic transcription factors (E2F1, MYC, AR-GATA2), linking nuclear transport capacity to cancer aggressiveness.\",\n      \"evidence\": \"Loss-of-function genetic screen, nuclear transport assays, importazole inhibition, patient-derived xenografts\",\n      \"pmids\": [\"30100187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cargo selectivity is direct or via altered NPC composition not resolved\", \"Mechanism distinguishing oncogenic cargoes from bulk import unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended POM121's import-regulatory role to immune signaling, showing it restrains nuclear accumulation of phospho-p65 to dampen NF-κB-driven inflammation.\",\n      \"evidence\": \"Macrophage-specific conditional knockout mice, LPS challenge, phospho-p65 Western blot, cytokine measurement\",\n      \"pmids\": [\"30802453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interaction of POM121 with p65 import machinery not shown\", \"How POM121 selectively limits p65 import unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified POM121 loss as the initiating event in a nucleoporin-depletion cascade and Ran disruption in C9orf72 ALS/FTD neurons, positioning it at the apex of nucleocytoplasmic transport failure.\",\n      \"evidence\": \"Super-resolution SIM of nucleoporins and siRNA in iPSC-derived neurons\",\n      \"pmids\": [\"32673563\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which G4C2 RNA reduces POM121 not defined\", \"Causal chain from POM121 loss to downstream Nup decrease not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined SIGMAR1 as a chaperone that supports POM121-dependent KPNB1 recruitment to enable TFEB nuclear import and autophagy, with disruption in C9orf72 disease.\",\n      \"evidence\": \"Co-IP, overexpression/siRNA, pridopidine activation, nuclear TFEB/KPNB1/LC3-II Western blots\",\n      \"pmids\": [\"35507432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical nature of SIGMAR1-POM121 chaperoning not structurally defined\", \"Single-lab Co-IP without reciprocal structural validation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed POM121 cytoplasmically sequesters PPARγ via a region downstream of its NLS, so that POM121 loss enforces PPARγ nuclear accumulation and growth arrest in colorectal cancer.\",\n      \"evidence\": \"CRISPR/Cas9 and siRNA silencing, nuclear fractionation, target gene expression, peptide interaction mapping\",\n      \"pmids\": [\"38177114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding affinity and structure of POM121-PPARγ interaction not determined\", \"Generality of cytoplasmic sequestration versus import gating unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reported a pathological structural repositioning of POM121 from the nuclear ring to the inner ring in C9orf72 ALS neurons, hinting at architectural remodeling of the NPC under disease.\",\n      \"evidence\": \"pan-Expansion Microscopy with machine-learning NPC sub-ring segmentation (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single imaging method in a preprint with no functional follow-up\", \"Functional consequence of repositioning unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a Sigma-1R/POM121/ATF3 protective axis in which poly-PR-induced POM121 loss mislocalizes ATF3 and damages the NE, while POM121 restoration rescues toxicity.\",\n      \"evidence\": \"siRNA/overexpression in NSC-34 cells, AAV-poly-PR mouse model, nuclear fractionation, ATF3 immunofluorescence, viability assays\",\n      \"pmids\": [\"40480424\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Sigma-1R-mediated POM121 stabilization under oxidative stress not biochemically defined\", \"Whether ATF3 mislocalization is direct POM121-dependent import not shown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established post-translational and transcriptional control of POM121 abundance: O-GlcNAcylation at Ser199 blocks TRIM21-mediated degradation, and H3K18 lactylation upregulates transcription, both increasing POM121-driven oncogenic import.\",\n      \"evidence\": \"MS site mapping with Ser199 mutagenesis, POM121-TRIM21 Co-IP and ubiquitination assays, c-MYC import assays; ChIP and dual-luciferase reporter with LDHA/LDHB silencing and rescue\",\n      \"pmids\": [\"41629644\", \"41864048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether OGT and lactylation pathways converge on the same POM121 pool not addressed\", \"Structural impact of Ser199 modification on TRIM21 binding not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How POM121 achieves cargo selectivity — distinguishing specific oncogenic and signaling transcription factors from bulk nuclear import — and how its dual roles in NPC architecture versus selective import are mechanistically separated remain open.\",\n      \"evidence\": \"No direct experimental resolution in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of POM121 cargo-discriminating interfaces\", \"Relationship between altered NPC composition and import selectivity unresolved\", \"Whether disease-associated import defects reflect loss of structural seeding or loss of import gating not separated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 5, 7]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [11, 12, 14]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [14, 15, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 4, 11]},\n      {\"term_id\": \"GO:0005643\", \"supporting_discovery_ids\": [5, 6, 7]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [11, 14, 18]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [4, 5, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [14, 16, 21]}\n    ],\n    \"complexes\": [\"Nuclear pore complex (NPC)\"],\n    \"partners\": [\"NUP107\", \"NUP62\", \"NUP358\", \"SUN1\", \"KPNB1\", \"SIGMAR1\", \"TRIM21\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}