{"gene":"SLC5A5","run_date":"2026-06-10T07:46:34","timeline":{"discoveries":[{"year":1996,"finding":"NIS (SLC5A5) was isolated by expression cloning in Xenopus laevis oocytes, establishing it as the plasma membrane protein mediating active iodide transport into thyroid follicular cells.","method":"Expression cloning in Xenopus oocytes","journal":"Nature (referenced in corpus reviews)","confidence":"High","confidence_rationale":"Tier 1 / Strong — expression cloning with functional reconstitution, widely replicated and foundational; cited across multiple independent review papers in the corpus","pmids":["12588808","24311738","9672241"],"is_preprint":false},{"year":1998,"finding":"NIS mediates electrogenic active transport with a stoichiometry of 2 Na+ ions co-transported per 1 iodide ion, as determined by electrophysiological analysis.","method":"Electrophysiological analysis (two-electrode voltage clamp and related assays)","journal":"Journal of bioenergetics and biomembranes","confidence":"High","confidence_rationale":"Tier 1 / Strong — electrophysiological functional reconstitution, replicated across multiple labs and confirmed in subsequent reviews","pmids":["9672241","12588808","24311738"],"is_preprint":false},{"year":2007,"finding":"NIS actively transports perchlorate (ClO4-) as a substrate (not merely a competitive inhibitor), but with an electroneutral Na+/ClO4- stoichiometry—different from the electrogenic 2 Na+/I- stoichiometry—demonstrating that NIS translocates different substrates with different stoichiometries.","method":"In vitro iodide/perchlorate uptake assays, in vivo translocation to milk, mathematical flux modeling","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro and in vivo assays with mathematical modeling in a single rigorous study; novel mechanistic finding replicated by two independent approaches","pmids":["18077370"],"is_preprint":false},{"year":2004,"finding":"The Q267E NIS mutation causes congenital iodide transport defect (ITD) by reducing the catalytic turnover number (lower Vmax) rather than by preventing plasma membrane targeting; neutral substitutions at position 267 are compatible with partial activity, but any charged residue (of either polarity) other than Gln renders NIS inactive without affecting expression or membrane targeting.","method":"Site-directed mutagenesis, iodide uptake assays, COS-7 cell transfection, immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in mammalian cells combined with systematic mutagenesis and quantitative transport assays in a single focused study","pmids":["14734652"],"is_preprint":false},{"year":2003,"finding":"NIS is selectively targeted to the basolateral membrane of thyroid follicular cells, enabling vectorial iodide transport from blood to the follicular lumen, as established by immunolocalization and functional fractionation studies.","method":"Immunohistochemistry, immunofluorescence, membrane fractionation","journal":"Endocrine reviews","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct subcellular localization with functional consequence (directional transport), widely replicated across multiple labs","pmids":["12588808"],"is_preprint":false},{"year":2003,"finding":"NIS-mediated iodide transport is driven by the electrochemical sodium gradient generated by the Na+/K+-ATPase; disruption of this gradient abolishes NIS function.","method":"Pharmacological inhibition of Na+/K+-ATPase combined with iodide uptake assays","journal":"Endocrine reviews","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional assay with defined inhibitor, replicated across multiple studies and referenced in independent reviews","pmids":["12588808","19196800"],"is_preprint":false},{"year":2015,"finding":"Glycosylation of NIS regulates its membrane translocation and radioiodine uptake: cAMP-stimulated glycosylation promotes NIS plasma membrane targeting and enhances iodide uptake, while inhibition of glycosylation with tunicamycin dramatically reduces NIS membrane localization and uptake.","method":"Confocal microscopy of NIS/tdTomato fusion protein, radioiodine uptake assay, immunoblot, tunicamycin inhibition, cAMP stimulation in stably transfected HeLa cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live-cell imaging of subcellular localization coupled to functional radioiodine uptake assay with pharmacological perturbation; single lab, two orthogonal methods","pmids":["26599396"],"is_preprint":false},{"year":2021,"finding":"A G561E missense variant in NIS impairs recognition of an adjacent tryptophan-acidic (W-acidic) motif by kinesin light chain 2 (KLC2), blocking NIS maturation beyond the endoplasmic reticulum and reducing plasma membrane targeting and iodide accumulation; KLC2 knockdown phenocopies this defect in rat thyroid cells and reduces thyroid hormone synthesis in zebrafish larvae.","method":"Site-directed mutagenesis, iodide uptake assay, co-immunoprecipitation (NIS–KLC2 interaction), KLC2 siRNA knockdown in rat thyroid cells, morpholino knockdown in zebrafish, structural bioinformatics","journal":"The Journal of clinical endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical interaction (Co-IP), loss-of-function in two independent model systems (cell and zebrafish), mutagenesis, and functional iodide uptake assay in one study","pmids":["33912899"],"is_preprint":false},{"year":2012,"finding":"NIS (SLC5A5) interacts physically with the Rho guanine nucleotide exchange factor LARG (leukemia-associated RhoA GEF), thereby activating RhoA signaling to enhance cancer cell migration and invasion independently of its ion transport activity; sequestration of NIS in intracellular organelles (as observed in many cancers) further increases cell motility and invasiveness.","method":"Co-immunoprecipitation (NIS–LARG interaction), cell migration and invasion assays, intracellular NIS targeting constructs in cancer cell lines","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing NIS–LARG binding plus defined functional phenotype (migration/invasion), single lab","pmids":["22962269"],"is_preprint":false},{"year":2016,"finding":"Systematic mutagenesis of trafficking motifs in human NIS identified that mutation of an internal PDZ-binding motif at position 121 completely abolishes NIS expression at the plasma membrane; mutation at position 178 (SH2/tyrosine-based motif) impairs iodide uptake; C-terminal domain motifs are dispensable for membrane targeting.","method":"Site-directed mutagenesis of sorting motifs combined with iodide uptake assays and cell surface expression analysis","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic in vitro mutagenesis with functional iodide uptake readout; comprehensive mapping in a single study","pmids":["26831514"],"is_preprint":false},{"year":2010,"finding":"Retinoic acid (tRA) directly induces NIS transcription through retinoic acid receptor alpha (RARα)/retinoid-X-receptor (RXR) heterodimers binding to conserved retinoic acid response elements (RAREs) located within the first intron of the NIS gene, as demonstrated by ChIP and in vitro/in vivo DNA-protein interaction assays in MCF-7 breast cancer cells.","method":"Chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), reporter gene assays, luciferase transcription assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP with direct protein–DNA interaction assays and reporter gene functional validation; multiple orthogonal methods in one study","pmids":["20123735"],"is_preprint":false},{"year":2013,"finding":"NIS is a direct transcriptional target of p53-family members (p53, p63, p73): these factors bind p53-responsive element clusters in the NIS core promoter (shown by ChIP), stimulate NIS promoter activity and endogenous NIS mRNA/protein expression, and doxorubicin-induced DNA damage strongly increases p53/p73 binding to the NIS promoter in HCC and CCA cells. NIS silencing reduces doxorubicin-induced apoptosis in HCC cells.","method":"Chromatin immunoprecipitation (ChIP), siRNA knockdown, reporter gene assay, Western blot, RT-PCR in liver cancer cell lines","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP demonstrating direct promoter occupancy plus functional reporter assay and siRNA loss-of-function with apoptosis readout; multiple orthogonal methods in one study","pmids":["24052075"],"is_preprint":false},{"year":2014,"finding":"BRAF V600E promotes NIS silencing via histone deacetylation at critical regulatory regions (nucleotides -297/-107 in rat, -692/-370 in human NIS promoter); pharmacological inhibition of BRAF V600E or MEK restores histone acetylation at the NIS promoter, and HDAC inhibitor SAHA reverses deacetylation and restores NIS expression.","method":"Chromatin immunoprecipitation (ChIP) for H3K9/14ac, H3K18ac, H4ac, H4K16ac; stable BRAF V600E transfection in PCCL3 cells; BRAF and MEK inhibitors in BCPAP cells","journal":"Endocrine-related cancer","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP with multiple histone marks, pharmacological and genetic manipulation, single lab but multiple orthogonal approaches","pmids":["24243688"],"is_preprint":false},{"year":2013,"finding":"AMPK modulates NIS expression and iodide uptake in thyroid cells via the CRE (cAMP response element) in the NIS promoter: AMPK activation (metformin) reduces NIS promoter activity via CRE and decreases iodide uptake, while AMPK inhibition (compound C) stimulates CRE-mediated NIS transcription and iodide uptake both in vitro and in vivo.","method":"NIS promoter-reporter constructs with isolated CRE and NF-κB elements, iodide uptake assays, NIS Western blot, in vivo mouse studies, AMPK-α1 knockout mice","journal":"Thyroid","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter-reporter functional assay identifying CRE as the regulatory element, combined with in vivo pharmacological and genetic knockout validation; single lab","pmids":["23819433"],"is_preprint":false},{"year":2015,"finding":"miR-146b-3p directly binds the 3'-UTR of both PAX8 and NIS mRNAs, inhibiting their translation and reducing iodide uptake; miR-146b and PAX8 mutually regulate each other, forming a regulatory circuit governing thyroid cell differentiation in papillary thyroid carcinoma.","method":"3'-UTR luciferase reporter assay (direct miR-146b-3p binding to PAX8 and NIS 3'-UTR), next-generation sequencing, mRNA sequencing, iodide uptake assay in thyroid cancer cell lines","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct 3'-UTR reporter assay demonstrating miRNA-mRNA binding with functional iodide uptake consequence; multiple orthogonal methods in a single study","pmids":["26282166"],"is_preprint":false},{"year":2006,"finding":"In MCF-7 breast cancer cells, hydrocortisone and ATP (via purinergic signaling) each markedly stimulate retinoic acid-induced NIS protein expression and plasma membrane targeting, increasing iodide uptake by at least 100%; conversely, forskolin (adenylyl cyclase activator) decreases retinoic acid-induced NIS expression in MCF-7 cells—opposite to its effect in thyroid cells—indicating tissue-specific cAMP regulation of NIS.","method":"Iodide uptake assay, Western blot, pharmacological stimulation in MCF-7 cells","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional iodide uptake and protein expression assays with multiple pharmacological perturbations; single lab","pmids":["16439463"],"is_preprint":false},{"year":2014,"finding":"A newly identified distal NIS enhancer (NDE), located at -2152/-1887 relative to ATG, regulates NIS expression via DNA methylation; hypermethylation of this enhancer in thyroid tumors correlates inversely with NIS mRNA expression, and demethylation with 5-Aza restores NIS mRNA, protein, and iodide uptake.","method":"Bisulfite sequencing, reporter gene assay (confirming enhancer activity), 5-Aza demethylation treatment with RT-PCR, Western blot, and 125I uptake assay in matched tumor/non-tumor samples","journal":"The Journal of clinical endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reporter gene assay confirming enhancer function, bisulfite sequencing, and pharmacological demethylation with functional iodide uptake readout; multiple orthogonal methods in one study","pmids":["24432988"],"is_preprint":false},{"year":2009,"finding":"NIS is expressed at the basolateral membrane of gastric mucin-producing epithelial cells; NIS expression is absent in gastric cancer and in Barrett mucosa with intestinal metaplasia, but present in Barrett mucosa with fundic/junctional columnar metaplasia, establishing NIS localization and its loss during intestinalization or malignant transformation of gastric mucosa.","method":"Immunohistochemistry and immunoblot in 155 gastrointestinal tissue samples from 83 patients","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunohistochemistry in large tissue cohort with paired immunoblot validation; single lab","pmids":["17214887"],"is_preprint":false},{"year":2005,"finding":"Overexpression of transcription factor Pax8 in anaplastic thyroid carcinoma ARO cells reactivates NIS expression and partial membrane targeting (confirmed by immunofluorescence and Western blot), restoring partial radioiodide uptake ability, demonstrating Pax8 as a transcriptional regulator required for NIS expression.","method":"Stable transfection with Pax8 expression vector, quantitative RT-PCR, Western blot, immunofluorescence, iodide uptake assay","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with multiple readouts (mRNA, protein, localization, function); single lab","pmids":["16029487"],"is_preprint":false},{"year":2009,"finding":"Radiation-induced stunning of thyroid cells reduces iodide transport and NIS mRNA expression; all tested NIS-transported radionuclides (123I, 131I, 99mTc, 211At) caused downregulation, with the degree of NIS mRNA reduction related to the biological effectiveness of the radiation type. 211At caused the highest per-dose stunning but also the only full recovery of transport.","method":"Quantitative RT-PCR for NIS mRNA, iodide transport assay in TSH-stimulated thyroid cell monolayers exposed to defined absorbed doses of radionuclides","journal":"Journal of nuclear medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — controlled in vitro irradiation with quantitative mRNA and functional transport readouts; single lab but systematic comparison across multiple radionuclides","pmids":["19525464"],"is_preprint":false},{"year":2011,"finding":"NIS protein is expressed in germinal and Leydig cells of normal testis (but not Sertoli cells), predominantly in the cytosol compartment rather than at the plasma membrane, as determined by Western blot and immunohistochemistry in mouse, rat, and human testicular tissue.","method":"Quantitative RT-PCR, Western blot, immunohistochemistry in fetal and adult testicular tissue from three species","journal":"Endocrine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization by IHC and Western blot across multiple species, but no functional consequence established; single lab","pmids":["21499816"],"is_preprint":false},{"year":1999,"finding":"Six NIS mutations causing congenital iodide transport defect (G93R, Q267E, C272X, T354P, Y531X, G543E) produce NIS proteins with no or minimal iodide transport activity when expressed in mammalian cells; critically, T354P does not prevent membrane targeting but specifically impairs transport function, while co-transfection of mutant with wild-type NIS shows no dominant-negative interference.","method":"Mammalian cell transfection, iodide uptake assay, co-transfection with wild-type NIS","journal":"Biochimie","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional in vitro characterization of multiple disease mutants with cell-based uptake assays; replicated and extended by subsequent study (PMID 14734652)","pmids":["10403177"],"is_preprint":false}],"current_model":"NIS (SLC5A5) is a plasma membrane glycoprotein that mediates active, electrogenic co-transport of 2 Na+ per I- into thyroid follicular cells (and several extrathyroidal tissues) driven by the Na+/K+-ATPase-maintained sodium gradient; it is selectively targeted to the basolateral membrane via trafficking motifs including a critical PDZ-binding site at position 121 and a KLC2-recognized W-acidic motif near the C-terminus; it can transport alternative substrates such as perchlorate with altered (electroneutral) stoichiometry; its expression is transcriptionally regulated by TSH/cAMP (via CRE), Pax8, p53-family members, retinoic acid receptors acting through intronic RAREs, and is suppressed by BRAF V600E through histone deacetylation at its promoter and by miR-146b-3p through 3'-UTR-mediated translational repression; beyond ion transport, NIS physically interacts with the Rho-GEF LARG to modulate RhoA-dependent cell migration and invasion."},"narrative":{"mechanistic_narrative":"SLC5A5 (NIS) is the plasma membrane glycoprotein that mediates active iodide accumulation in thyroid follicular cells, originally defined by expression cloning of iodide transport activity in Xenopus oocytes [PMID:12588808, PMID:24311738, PMID:9672241]. It catalyzes electrogenic Na+/I- symport with a stoichiometry of 2 Na+ per I-, energized by the electrochemical Na+ gradient that the Na+/K+-ATPase maintains; collapsing this gradient abolishes transport [PMID:9672241, PMID:12588808, PMID:24311738, PMID:19196800]. NIS is a polyspecific transporter that can also translocate perchlorate, but does so with a distinct electroneutral Na+/ClO4- stoichiometry, demonstrating substrate-dependent coupling [PMID:18077370]. Vectorial blood-to-lumen iodide transport requires selective basolateral targeting [PMID:12588808], which depends on N-glycosylation and cAMP-stimulated maturation [PMID:26599396], an internal PDZ-binding motif at position 121 whose mutation abolishes surface expression [PMID:26831514], and a C-terminal W-acidic motif recognized by kinesin light chain 2 (KLC2) that licenses ER exit; the G561E variant disrupts KLC2 recognition and blocks NIS maturation, with KLC2 loss reducing iodide accumulation in thyroid cells and thyroid hormone synthesis in zebrafish [PMID:33912899]. Congenital iodide transport defect arises from point mutations such as Q267E and T354P that lower catalytic turnover without preventing membrane targeting [PMID:14734652, PMID:10403177]. NIS transcription is controlled by a network of regulators acting through defined promoter and intronic elements: Pax8 [PMID:16029487], p53-family members at p53-responsive elements [PMID:24052075], retinoic acid receptor/RXR heterodimers at intronic RAREs [PMID:20123735], and CRE-dependent cAMP/AMPK input [PMID:23819433], while it is silenced in cancer by BRAF V600E-driven histone deacetylation [PMID:24243688], distal enhancer DNA methylation [PMID:24432988], and miR-146b-3p-mediated 3'-UTR translational repression [PMID:26282166]. Beyond ion transport, NIS physically binds the Rho-GEF LARG to activate RhoA signaling and promote cancer cell migration and invasion, a transport-independent function enhanced when NIS is sequestered intracellularly [PMID:22962269].","teleology":[{"year":1996,"claim":"Established the molecular identity of the long-sought thyroid iodide transporter, converting a physiological activity into a defined gene product.","evidence":"Expression cloning in Xenopus oocytes with functional iodide uptake","pmids":["12588808","24311738","9672241"],"confidence":"High","gaps":["Did not resolve transport stoichiometry or driving force","No structural model of the transporter"]},{"year":1998,"claim":"Defined the energetic mechanism of iodide accumulation by quantifying the ion coupling, explaining how NIS concentrates iodide against its gradient.","evidence":"Electrophysiological analysis (two-electrode voltage clamp)","pmids":["9672241","12588808","24311738"],"confidence":"High","gaps":["Did not address whether other substrates share the same stoichiometry","No residue-level mechanism of ion coupling"]},{"year":2003,"claim":"Showed that NIS function is coupled to the Na+/K+-ATPase-maintained gradient and that the protein is selectively basolateral, linking energetics to vectorial transport physiology.","evidence":"Na+/K+-ATPase inhibition with uptake assays; immunolocalization and membrane fractionation","pmids":["12588808","19196800"],"confidence":"High","gaps":["Did not identify the trafficking determinants of basolateral sorting"]},{"year":2004,"claim":"Distinguished catalytic from trafficking defects in disease mutants, showing that ITD mutations such as Q267E reduce turnover rather than block membrane targeting.","evidence":"Site-directed mutagenesis and iodide uptake in COS-7 cells with immunofluorescence","pmids":["14734652"],"confidence":"High","gaps":["Mechanism by which position 267 controls turnover unresolved","No structural basis for charge intolerance"]},{"year":2007,"claim":"Demonstrated that NIS is polyspecific and that coupling stoichiometry is substrate-dependent, reframing perchlorate as a transported substrate rather than a pure inhibitor.","evidence":"In vitro/in vivo uptake assays with mathematical flux modeling","pmids":["18077370"],"confidence":"High","gaps":["Structural basis for differential stoichiometry unknown"]},{"year":2016,"claim":"Systematically mapped trafficking motifs, identifying the position-121 PDZ-binding motif as essential for surface expression and position 178 for transport.","evidence":"Mutagenesis of sorting motifs with surface expression and iodide uptake readouts","pmids":["26831514"],"confidence":"High","gaps":["Identity of the PDZ partner not established","C-terminal motif function clarified only later"]},{"year":2021,"claim":"Identified KLC2 as a trafficking partner recognizing a C-terminal W-acidic motif required for NIS ER exit, providing a molecular route for a disease variant.","evidence":"Co-IP, mutagenesis, KLC2 siRNA in rat thyroid cells, and zebrafish morpholino knockdown","pmids":["33912899"],"confidence":"High","gaps":["Reconciliation with earlier finding that C-terminal motifs were dispensable for targeting","No structure of the NIS-KLC2 interface"]},{"year":2012,"claim":"Revealed a transport-independent role for NIS in promoting cancer cell motility through LARG/RhoA signaling, expanding NIS function beyond ion transport.","evidence":"Co-IP of NIS-LARG plus migration/invasion assays in cancer cell lines","pmids":["22962269"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation in multiple systems","Structural basis of NIS-LARG binding unknown","In vivo metastasis relevance not established"]},{"year":null,"claim":"How NIS trafficking, transport catalysis, and its non-canonical LARG/RhoA signaling are integrated at the structural level, and how cytosolic NIS in extrathyroidal tissues functions, remain open.","evidence":"No discovery in the corpus resolves NIS atomic structure or the mechanistic switch between transport and signaling roles","pmids":[],"confidence":"Low","gaps":["No experimental structure","Function of cytosolic NIS in testis undefined","Determinants selecting transport vs signaling roles unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,2,5]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,9,17]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[20]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1,2,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[10,11,12,13,16,18]}],"complexes":[],"partners":["KLC2","LARG","PAX8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92911","full_name":"Sodium/iodide cotransporter","aliases":["Natrium iodide transporter","Sodium-iodide symporter","Na(+)/I(-) symporter","Solute carrier family 5 member 5"],"length_aa":643,"mass_kda":68.7,"function":"Sodium:iodide symporter that mediates the transport of iodide into the thyroid gland (PubMed:12488351, PubMed:18372236, PubMed:18708479, PubMed:20797386, PubMed:31310151, PubMed:32084174, PubMed:8806637, PubMed:9329364). Can also mediate the transport of chlorate, thiocynate, nitrate and selenocynate (PubMed:12488351)","subcellular_location":"Cell membrane; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q92911/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC5A5","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC5A5","total_profiled":1310},"omim":[{"mim_id":"614589","title":"SKI3 SUBUNIT OF SUPERKILLER COMPLEX; SKIC3","url":"https://www.omim.org/entry/614589"},{"mim_id":"608044","title":"SOLUTE CARRIER FAMILY 5 (IODIDE TRANSPORTER), MEMBER 8; SLC5A8","url":"https://www.omim.org/entry/608044"},{"mim_id":"606765","title":"THYROID PEROXIDASE; TPO","url":"https://www.omim.org/entry/606765"},{"mim_id":"603372","title":"THYROID-STIMULATING HORMONE RECEPTOR; TSHR","url":"https://www.omim.org/entry/603372"},{"mim_id":"601843","title":"SOLUTE CARRIER FAMILY 5 (SODIUM IODIDE SYMPORTER), MEMBER 5; SLC5A5","url":"https://www.omim.org/entry/601843"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"choroid plexus","ntpm":134.2},{"tissue":"salivary gland","ntpm":60.7},{"tissue":"stomach 1","ntpm":55.5}],"url":"https://www.proteinatlas.org/search/SLC5A5"},"hgnc":{"alias_symbol":["NIS"],"prev_symbol":[]},"alphafold":{"accession":"Q92911","domains":[{"cath_id":"1.20.1730.10","chopping":"58-414","consensus_level":"high","plddt":91.4592,"start":58,"end":414}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92911","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92911-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92911-F1-predicted_aligned_error_v6.png","plddt_mean":81.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC5A5","jax_strain_url":"https://www.jax.org/strain/search?query=SLC5A5"},"sequence":{"accession":"Q92911","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92911.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92911/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92911"}},"corpus_meta":[{"pmid":"12588808","id":"PMC_12588808","title":"The sodium/iodide Symporter (NIS): characterization, regulation, and medical significance.","date":"2003","source":"Endocrine reviews","url":"https://pubmed.ncbi.nlm.nih.gov/12588808","citation_count":611,"is_preprint":false},{"pmid":"24311738","id":"PMC_24311738","title":"The Na+/I- symporter (NIS): mechanism and medical impact.","date":"2013","source":"Endocrine reviews","url":"https://pubmed.ncbi.nlm.nih.gov/24311738","citation_count":215,"is_preprint":false},{"pmid":"28192058","id":"PMC_28192058","title":"The Sodium/Iodide Symporter (NIS): Molecular Physiology and Preclinical and Clinical Applications.","date":"2017","source":"Annual review of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28192058","citation_count":202,"is_preprint":false},{"pmid":"19196800","id":"PMC_19196800","title":"Minireview: The sodium-iodide symporter NIS and pendrin in iodide homeostasis of the thyroid.","date":"2009","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/19196800","citation_count":146,"is_preprint":false},{"pmid":"22750642","id":"PMC_22750642","title":"The sodium iodide symporter (NIS): regulation and approaches to targeting for cancer therapeutics.","date":"2012","source":"Pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/22750642","citation_count":144,"is_preprint":false},{"pmid":"18077370","id":"PMC_18077370","title":"The Na+/I symporter (NIS) mediates electroneutral active transport of the environmental pollutant perchlorate.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18077370","citation_count":140,"is_preprint":false},{"pmid":"15062574","id":"PMC_15062574","title":"Advances in Na(+)/I(-) symporter (NIS) research in the thyroid and beyond.","date":"2003","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/15062574","citation_count":130,"is_preprint":false},{"pmid":"33995657","id":"PMC_33995657","title":"Molecular mechanisms of radioactive iodine refractoriness in differentiated thyroid cancer: Impaired sodium iodide symporter (NIS) expression owing to altered signaling pathway activity and intracellular localization of NIS.","date":"2021","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/33995657","citation_count":125,"is_preprint":false},{"pmid":"12475396","id":"PMC_12475396","title":"Increased expression of AP2 and Sp1 transcription factors in human thyroid tumors: a role in NIS expression regulation?","date":"2002","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/12475396","citation_count":109,"is_preprint":false},{"pmid":"22263922","id":"PMC_22263922","title":"The sodium iodide symporter (NIS) as an imaging reporter for gene, viral, and cell-based therapies.","date":"2012","source":"Current gene 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management","url":"https://pubmed.ncbi.nlm.nih.gov/35751232","citation_count":14,"is_preprint":false},{"pmid":"20300827","id":"PMC_20300827","title":"Stimulation of retinoic acid-induced functional sodium iodide symporter (NIS) expression and cytotoxicity of ¹³¹I by carbamazepine in breast cancer cells.","date":"2010","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/20300827","citation_count":14,"is_preprint":false},{"pmid":"39702735","id":"PMC_39702735","title":"NIS-Seq enables cell-type-agnostic optical perturbation screening.","date":"2024","source":"Nature biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/39702735","citation_count":13,"is_preprint":false},{"pmid":"20186172","id":"PMC_20186172","title":"Enhanced anti-tumor effects of combined MDR1 RNA interference and human sodium/iodide symporter (NIS) radioiodine gene therapy using an adenoviral system in a colon cancer model.","date":"2010","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/20186172","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52279,"output_tokens":5467,"usd":0.119421,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14002,"output_tokens":2918,"usd":0.07148,"stage2_stop_reason":"end_turn"},"total_usd":0.190901,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"NIS (SLC5A5) was isolated by expression cloning in Xenopus laevis oocytes, establishing it as the plasma membrane protein mediating active iodide transport into thyroid follicular cells.\",\n      \"method\": \"Expression cloning in Xenopus oocytes\",\n      \"journal\": \"Nature (referenced in corpus reviews)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — expression cloning with functional reconstitution, widely replicated and foundational; cited across multiple independent review papers in the corpus\",\n      \"pmids\": [\"12588808\", \"24311738\", \"9672241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"NIS mediates electrogenic active transport with a stoichiometry of 2 Na+ ions co-transported per 1 iodide ion, as determined by electrophysiological analysis.\",\n      \"method\": \"Electrophysiological analysis (two-electrode voltage clamp and related assays)\",\n      \"journal\": \"Journal of bioenergetics and biomembranes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — electrophysiological functional reconstitution, replicated across multiple labs and confirmed in subsequent reviews\",\n      \"pmids\": [\"9672241\", \"12588808\", \"24311738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NIS actively transports perchlorate (ClO4-) as a substrate (not merely a competitive inhibitor), but with an electroneutral Na+/ClO4- stoichiometry—different from the electrogenic 2 Na+/I- stoichiometry—demonstrating that NIS translocates different substrates with different stoichiometries.\",\n      \"method\": \"In vitro iodide/perchlorate uptake assays, in vivo translocation to milk, mathematical flux modeling\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro and in vivo assays with mathematical modeling in a single rigorous study; novel mechanistic finding replicated by two independent approaches\",\n      \"pmids\": [\"18077370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The Q267E NIS mutation causes congenital iodide transport defect (ITD) by reducing the catalytic turnover number (lower Vmax) rather than by preventing plasma membrane targeting; neutral substitutions at position 267 are compatible with partial activity, but any charged residue (of either polarity) other than Gln renders NIS inactive without affecting expression or membrane targeting.\",\n      \"method\": \"Site-directed mutagenesis, iodide uptake assays, COS-7 cell transfection, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in mammalian cells combined with systematic mutagenesis and quantitative transport assays in a single focused study\",\n      \"pmids\": [\"14734652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NIS is selectively targeted to the basolateral membrane of thyroid follicular cells, enabling vectorial iodide transport from blood to the follicular lumen, as established by immunolocalization and functional fractionation studies.\",\n      \"method\": \"Immunohistochemistry, immunofluorescence, membrane fractionation\",\n      \"journal\": \"Endocrine reviews\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct subcellular localization with functional consequence (directional transport), widely replicated across multiple labs\",\n      \"pmids\": [\"12588808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NIS-mediated iodide transport is driven by the electrochemical sodium gradient generated by the Na+/K+-ATPase; disruption of this gradient abolishes NIS function.\",\n      \"method\": \"Pharmacological inhibition of Na+/K+-ATPase combined with iodide uptake assays\",\n      \"journal\": \"Endocrine reviews\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional assay with defined inhibitor, replicated across multiple studies and referenced in independent reviews\",\n      \"pmids\": [\"12588808\", \"19196800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Glycosylation of NIS regulates its membrane translocation and radioiodine uptake: cAMP-stimulated glycosylation promotes NIS plasma membrane targeting and enhances iodide uptake, while inhibition of glycosylation with tunicamycin dramatically reduces NIS membrane localization and uptake.\",\n      \"method\": \"Confocal microscopy of NIS/tdTomato fusion protein, radioiodine uptake assay, immunoblot, tunicamycin inhibition, cAMP stimulation in stably transfected HeLa cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live-cell imaging of subcellular localization coupled to functional radioiodine uptake assay with pharmacological perturbation; single lab, two orthogonal methods\",\n      \"pmids\": [\"26599396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A G561E missense variant in NIS impairs recognition of an adjacent tryptophan-acidic (W-acidic) motif by kinesin light chain 2 (KLC2), blocking NIS maturation beyond the endoplasmic reticulum and reducing plasma membrane targeting and iodide accumulation; KLC2 knockdown phenocopies this defect in rat thyroid cells and reduces thyroid hormone synthesis in zebrafish larvae.\",\n      \"method\": \"Site-directed mutagenesis, iodide uptake assay, co-immunoprecipitation (NIS–KLC2 interaction), KLC2 siRNA knockdown in rat thyroid cells, morpholino knockdown in zebrafish, structural bioinformatics\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical interaction (Co-IP), loss-of-function in two independent model systems (cell and zebrafish), mutagenesis, and functional iodide uptake assay in one study\",\n      \"pmids\": [\"33912899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NIS (SLC5A5) interacts physically with the Rho guanine nucleotide exchange factor LARG (leukemia-associated RhoA GEF), thereby activating RhoA signaling to enhance cancer cell migration and invasion independently of its ion transport activity; sequestration of NIS in intracellular organelles (as observed in many cancers) further increases cell motility and invasiveness.\",\n      \"method\": \"Co-immunoprecipitation (NIS–LARG interaction), cell migration and invasion assays, intracellular NIS targeting constructs in cancer cell lines\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing NIS–LARG binding plus defined functional phenotype (migration/invasion), single lab\",\n      \"pmids\": [\"22962269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Systematic mutagenesis of trafficking motifs in human NIS identified that mutation of an internal PDZ-binding motif at position 121 completely abolishes NIS expression at the plasma membrane; mutation at position 178 (SH2/tyrosine-based motif) impairs iodide uptake; C-terminal domain motifs are dispensable for membrane targeting.\",\n      \"method\": \"Site-directed mutagenesis of sorting motifs combined with iodide uptake assays and cell surface expression analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic in vitro mutagenesis with functional iodide uptake readout; comprehensive mapping in a single study\",\n      \"pmids\": [\"26831514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Retinoic acid (tRA) directly induces NIS transcription through retinoic acid receptor alpha (RARα)/retinoid-X-receptor (RXR) heterodimers binding to conserved retinoic acid response elements (RAREs) located within the first intron of the NIS gene, as demonstrated by ChIP and in vitro/in vivo DNA-protein interaction assays in MCF-7 breast cancer cells.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), reporter gene assays, luciferase transcription assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP with direct protein–DNA interaction assays and reporter gene functional validation; multiple orthogonal methods in one study\",\n      \"pmids\": [\"20123735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NIS is a direct transcriptional target of p53-family members (p53, p63, p73): these factors bind p53-responsive element clusters in the NIS core promoter (shown by ChIP), stimulate NIS promoter activity and endogenous NIS mRNA/protein expression, and doxorubicin-induced DNA damage strongly increases p53/p73 binding to the NIS promoter in HCC and CCA cells. NIS silencing reduces doxorubicin-induced apoptosis in HCC cells.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), siRNA knockdown, reporter gene assay, Western blot, RT-PCR in liver cancer cell lines\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP demonstrating direct promoter occupancy plus functional reporter assay and siRNA loss-of-function with apoptosis readout; multiple orthogonal methods in one study\",\n      \"pmids\": [\"24052075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BRAF V600E promotes NIS silencing via histone deacetylation at critical regulatory regions (nucleotides -297/-107 in rat, -692/-370 in human NIS promoter); pharmacological inhibition of BRAF V600E or MEK restores histone acetylation at the NIS promoter, and HDAC inhibitor SAHA reverses deacetylation and restores NIS expression.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for H3K9/14ac, H3K18ac, H4ac, H4K16ac; stable BRAF V600E transfection in PCCL3 cells; BRAF and MEK inhibitors in BCPAP cells\",\n      \"journal\": \"Endocrine-related cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP with multiple histone marks, pharmacological and genetic manipulation, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"24243688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"AMPK modulates NIS expression and iodide uptake in thyroid cells via the CRE (cAMP response element) in the NIS promoter: AMPK activation (metformin) reduces NIS promoter activity via CRE and decreases iodide uptake, while AMPK inhibition (compound C) stimulates CRE-mediated NIS transcription and iodide uptake both in vitro and in vivo.\",\n      \"method\": \"NIS promoter-reporter constructs with isolated CRE and NF-κB elements, iodide uptake assays, NIS Western blot, in vivo mouse studies, AMPK-α1 knockout mice\",\n      \"journal\": \"Thyroid\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter-reporter functional assay identifying CRE as the regulatory element, combined with in vivo pharmacological and genetic knockout validation; single lab\",\n      \"pmids\": [\"23819433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"miR-146b-3p directly binds the 3'-UTR of both PAX8 and NIS mRNAs, inhibiting their translation and reducing iodide uptake; miR-146b and PAX8 mutually regulate each other, forming a regulatory circuit governing thyroid cell differentiation in papillary thyroid carcinoma.\",\n      \"method\": \"3'-UTR luciferase reporter assay (direct miR-146b-3p binding to PAX8 and NIS 3'-UTR), next-generation sequencing, mRNA sequencing, iodide uptake assay in thyroid cancer cell lines\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct 3'-UTR reporter assay demonstrating miRNA-mRNA binding with functional iodide uptake consequence; multiple orthogonal methods in a single study\",\n      \"pmids\": [\"26282166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In MCF-7 breast cancer cells, hydrocortisone and ATP (via purinergic signaling) each markedly stimulate retinoic acid-induced NIS protein expression and plasma membrane targeting, increasing iodide uptake by at least 100%; conversely, forskolin (adenylyl cyclase activator) decreases retinoic acid-induced NIS expression in MCF-7 cells—opposite to its effect in thyroid cells—indicating tissue-specific cAMP regulation of NIS.\",\n      \"method\": \"Iodide uptake assay, Western blot, pharmacological stimulation in MCF-7 cells\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional iodide uptake and protein expression assays with multiple pharmacological perturbations; single lab\",\n      \"pmids\": [\"16439463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A newly identified distal NIS enhancer (NDE), located at -2152/-1887 relative to ATG, regulates NIS expression via DNA methylation; hypermethylation of this enhancer in thyroid tumors correlates inversely with NIS mRNA expression, and demethylation with 5-Aza restores NIS mRNA, protein, and iodide uptake.\",\n      \"method\": \"Bisulfite sequencing, reporter gene assay (confirming enhancer activity), 5-Aza demethylation treatment with RT-PCR, Western blot, and 125I uptake assay in matched tumor/non-tumor samples\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reporter gene assay confirming enhancer function, bisulfite sequencing, and pharmacological demethylation with functional iodide uptake readout; multiple orthogonal methods in one study\",\n      \"pmids\": [\"24432988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NIS is expressed at the basolateral membrane of gastric mucin-producing epithelial cells; NIS expression is absent in gastric cancer and in Barrett mucosa with intestinal metaplasia, but present in Barrett mucosa with fundic/junctional columnar metaplasia, establishing NIS localization and its loss during intestinalization or malignant transformation of gastric mucosa.\",\n      \"method\": \"Immunohistochemistry and immunoblot in 155 gastrointestinal tissue samples from 83 patients\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunohistochemistry in large tissue cohort with paired immunoblot validation; single lab\",\n      \"pmids\": [\"17214887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Overexpression of transcription factor Pax8 in anaplastic thyroid carcinoma ARO cells reactivates NIS expression and partial membrane targeting (confirmed by immunofluorescence and Western blot), restoring partial radioiodide uptake ability, demonstrating Pax8 as a transcriptional regulator required for NIS expression.\",\n      \"method\": \"Stable transfection with Pax8 expression vector, quantitative RT-PCR, Western blot, immunofluorescence, iodide uptake assay\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with multiple readouts (mRNA, protein, localization, function); single lab\",\n      \"pmids\": [\"16029487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Radiation-induced stunning of thyroid cells reduces iodide transport and NIS mRNA expression; all tested NIS-transported radionuclides (123I, 131I, 99mTc, 211At) caused downregulation, with the degree of NIS mRNA reduction related to the biological effectiveness of the radiation type. 211At caused the highest per-dose stunning but also the only full recovery of transport.\",\n      \"method\": \"Quantitative RT-PCR for NIS mRNA, iodide transport assay in TSH-stimulated thyroid cell monolayers exposed to defined absorbed doses of radionuclides\",\n      \"journal\": \"Journal of nuclear medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — controlled in vitro irradiation with quantitative mRNA and functional transport readouts; single lab but systematic comparison across multiple radionuclides\",\n      \"pmids\": [\"19525464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NIS protein is expressed in germinal and Leydig cells of normal testis (but not Sertoli cells), predominantly in the cytosol compartment rather than at the plasma membrane, as determined by Western blot and immunohistochemistry in mouse, rat, and human testicular tissue.\",\n      \"method\": \"Quantitative RT-PCR, Western blot, immunohistochemistry in fetal and adult testicular tissue from three species\",\n      \"journal\": \"Endocrine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization by IHC and Western blot across multiple species, but no functional consequence established; single lab\",\n      \"pmids\": [\"21499816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Six NIS mutations causing congenital iodide transport defect (G93R, Q267E, C272X, T354P, Y531X, G543E) produce NIS proteins with no or minimal iodide transport activity when expressed in mammalian cells; critically, T354P does not prevent membrane targeting but specifically impairs transport function, while co-transfection of mutant with wild-type NIS shows no dominant-negative interference.\",\n      \"method\": \"Mammalian cell transfection, iodide uptake assay, co-transfection with wild-type NIS\",\n      \"journal\": \"Biochimie\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional in vitro characterization of multiple disease mutants with cell-based uptake assays; replicated and extended by subsequent study (PMID 14734652)\",\n      \"pmids\": [\"10403177\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NIS (SLC5A5) is a plasma membrane glycoprotein that mediates active, electrogenic co-transport of 2 Na+ per I- into thyroid follicular cells (and several extrathyroidal tissues) driven by the Na+/K+-ATPase-maintained sodium gradient; it is selectively targeted to the basolateral membrane via trafficking motifs including a critical PDZ-binding site at position 121 and a KLC2-recognized W-acidic motif near the C-terminus; it can transport alternative substrates such as perchlorate with altered (electroneutral) stoichiometry; its expression is transcriptionally regulated by TSH/cAMP (via CRE), Pax8, p53-family members, retinoic acid receptors acting through intronic RAREs, and is suppressed by BRAF V600E through histone deacetylation at its promoter and by miR-146b-3p through 3'-UTR-mediated translational repression; beyond ion transport, NIS physically interacts with the Rho-GEF LARG to modulate RhoA-dependent cell migration and invasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC5A5 (NIS) is the plasma membrane glycoprotein that mediates active iodide accumulation in thyroid follicular cells, originally defined by expression cloning of iodide transport activity in Xenopus oocytes [#0]. It catalyzes electrogenic Na+/I- symport with a stoichiometry of 2 Na+ per I-, energized by the electrochemical Na+ gradient that the Na+/K+-ATPase maintains; collapsing this gradient abolishes transport [#1, #5]. NIS is a polyspecific transporter that can also translocate perchlorate, but does so with a distinct electroneutral Na+/ClO4- stoichiometry, demonstrating substrate-dependent coupling [#2]. Vectorial blood-to-lumen iodide transport requires selective basolateral targeting [#4], which depends on N-glycosylation and cAMP-stimulated maturation [#6], an internal PDZ-binding motif at position 121 whose mutation abolishes surface expression [#9], and a C-terminal W-acidic motif recognized by kinesin light chain 2 (KLC2) that licenses ER exit; the G561E variant disrupts KLC2 recognition and blocks NIS maturation, with KLC2 loss reducing iodide accumulation in thyroid cells and thyroid hormone synthesis in zebrafish [#7]. Congenital iodide transport defect arises from point mutations such as Q267E and T354P that lower catalytic turnover without preventing membrane targeting [#3, #21]. NIS transcription is controlled by a network of regulators acting through defined promoter and intronic elements: Pax8 [#18], p53-family members at p53-responsive elements [#11], retinoic acid receptor/RXR heterodimers at intronic RAREs [#10], and CRE-dependent cAMP/AMPK input [#13], while it is silenced in cancer by BRAF V600E-driven histone deacetylation [#12], distal enhancer DNA methylation [#16], and miR-146b-3p-mediated 3'-UTR translational repression [#14]. Beyond ion transport, NIS physically binds the Rho-GEF LARG to activate RhoA signaling and promote cancer cell migration and invasion, a transport-independent function enhanced when NIS is sequestered intracellularly [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the molecular identity of the long-sought thyroid iodide transporter, converting a physiological activity into a defined gene product.\",\n      \"evidence\": \"Expression cloning in Xenopus oocytes with functional iodide uptake\",\n      \"pmids\": [\"12588808\", \"24311738\", \"9672241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve transport stoichiometry or driving force\", \"No structural model of the transporter\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined the energetic mechanism of iodide accumulation by quantifying the ion coupling, explaining how NIS concentrates iodide against its gradient.\",\n      \"evidence\": \"Electrophysiological analysis (two-electrode voltage clamp)\",\n      \"pmids\": [\"9672241\", \"12588808\", \"24311738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address whether other substrates share the same stoichiometry\", \"No residue-level mechanism of ion coupling\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed that NIS function is coupled to the Na+/K+-ATPase-maintained gradient and that the protein is selectively basolateral, linking energetics to vectorial transport physiology.\",\n      \"evidence\": \"Na+/K+-ATPase inhibition with uptake assays; immunolocalization and membrane fractionation\",\n      \"pmids\": [\"12588808\", \"19196800\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the trafficking determinants of basolateral sorting\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Distinguished catalytic from trafficking defects in disease mutants, showing that ITD mutations such as Q267E reduce turnover rather than block membrane targeting.\",\n      \"evidence\": \"Site-directed mutagenesis and iodide uptake in COS-7 cells with immunofluorescence\",\n      \"pmids\": [\"14734652\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which position 267 controls turnover unresolved\", \"No structural basis for charge intolerance\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated that NIS is polyspecific and that coupling stoichiometry is substrate-dependent, reframing perchlorate as a transported substrate rather than a pure inhibitor.\",\n      \"evidence\": \"In vitro/in vivo uptake assays with mathematical flux modeling\",\n      \"pmids\": [\"18077370\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for differential stoichiometry unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Systematically mapped trafficking motifs, identifying the position-121 PDZ-binding motif as essential for surface expression and position 178 for transport.\",\n      \"evidence\": \"Mutagenesis of sorting motifs with surface expression and iodide uptake readouts\",\n      \"pmids\": [\"26831514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the PDZ partner not established\", \"C-terminal motif function clarified only later\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified KLC2 as a trafficking partner recognizing a C-terminal W-acidic motif required for NIS ER exit, providing a molecular route for a disease variant.\",\n      \"evidence\": \"Co-IP, mutagenesis, KLC2 siRNA in rat thyroid cells, and zebrafish morpholino knockdown\",\n      \"pmids\": [\"33912899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with earlier finding that C-terminal motifs were dispensable for targeting\", \"No structure of the NIS-KLC2 interface\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed a transport-independent role for NIS in promoting cancer cell motility through LARG/RhoA signaling, expanding NIS function beyond ion transport.\",\n      \"evidence\": \"Co-IP of NIS-LARG plus migration/invasion assays in cancer cell lines\",\n      \"pmids\": [\"22962269\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation in multiple systems\", \"Structural basis of NIS-LARG binding unknown\", \"In vivo metastasis relevance not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NIS trafficking, transport catalysis, and its non-canonical LARG/RhoA signaling are integrated at the structural level, and how cytosolic NIS in extrathyroidal tissues functions, remain open.\",\n      \"evidence\": \"No discovery in the corpus resolves NIS atomic structure or the mechanistic switch between transport and signaling roles\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experimental structure\", \"Function of cytosolic NIS in testis undefined\", \"Determinants selecting transport vs signaling roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 2, 5]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 9, 17]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 2, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [10, 11, 12, 13, 16, 18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KLC2\", \"LARG\", \"PAX8\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}