{"gene":"IK","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1994,"finding":"IK encodes a 19 kDa cytokine secreted by the leukemic cell line K562 and several cancer cells that inhibits IFN-gamma-induced HLA class II antigen expression. The gene maps to chromosome 2p15-p14, its mRNA is approximately 2.1 kb, and transient transfection of the IK cDNA into COS cells induces secretion of a biologically active 19 kDa protein recognized by a blocking monoclonal antibody. The nucleotide sequence showed no homology to known cytokines at the time.","method":"Protein purification, monoclonal antibody production, cDNA cloning and sequencing, transient transfection of COS cells, Western blot, chromosome mapping, functional inhibition assay (IFN-gamma-induced HLA-DR suppression in Colo 205 cells)","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods in a single study: purification, cloning, sequencing, functional rescue by transient transfection, and antibody-mediated neutralization of biological activity","pmids":["7970704"],"is_preprint":false},{"year":2006,"finding":"A truncated IK analog (tIK), translated from methionine at position 316, acts as a secretory protein and reduces IFN-gamma-induced HLA class II MHC expression through decreased expression of the class II MHC transcription activator (CIITA). In MRL/lpr mice, tIK treatment significantly reduced renal damage, decreased macrophage and T cell infiltration in kidneys, reduced IFN-gamma and IL-2 production, and decreased anti-DNA antibodies and circulating immune complexes, demonstrating that IK cytokine modulates autoimmune pathology via suppression of class II MHC-dependent immune activation.","method":"Truncated IK protein engineering, transfection into fibroblastoid cell line, subcutaneous injection into MRL/lpr mice, histological analysis of kidneys, flow cytometry for class II MHC expression on B cells and monocytes, ELISA for cytokines and antibodies","journal":"Arthritis and rheumatism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss/gain-of-function in vivo with multiple defined readouts (renal pathology, immune infiltration, cytokine levels, antibody titers, MHC expression) from a single lab","pmids":["17075801"],"is_preprint":false},{"year":2008,"finding":"Morpholino-mediated knockdown of the zebrafish ortholog of IK in zebrafish embryos results in myocardial contractile dysfunction, establishing that IK has a functional role in cardiac muscle contractility. This was demonstrated in a genetic epistasis/loss-of-function screen alongside HBEGF and SRA1 within a 600-kb linkage disequilibrium block on 5q31.2-3 associated with dilated cardiomyopathy.","method":"Morpholino antisense knockdown in zebrafish, cardiac contractility phenotype assessment, genetic association analysis in human populations","journal":"Genome research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single zebrafish morpholino knockdown experiment, phenotype reported but no mechanistic pathway placement beyond contractile dysfunction; single lab, no mammalian ortholog validation","pmids":["19064678"],"is_preprint":false}],"current_model":"IK (also called RER) encodes a secreted 19 kDa cytokine that inhibits IFN-gamma-induced HLA class II MHC antigen expression by suppressing class II MHC transcription activator (CIITA) levels; a truncated form of IK translated from an internal methionine is sufficient for secretion and biological activity, and IK has been shown to reduce autoimmune pathology in mouse models of lupus nephritis through class II MHC-dependent suppression of T cell and macrophage infiltration."},"narrative":{"mechanistic_narrative":"IK (also called RER) encodes a 19 kDa cytokine secreted by leukemic and cancer cell lines that inhibits IFN-gamma-induced HLA class II MHC antigen expression, identified through protein purification, cDNA cloning, and antibody-mediated neutralization of its biological activity [PMID:7970704]. Mechanistically, IK suppresses class II MHC expression by decreasing levels of the class II MHC transcription activator (CIITA), and a truncated form translated from an internal methionine (tIK) retains both secretion and this inhibitory activity [PMID:17075801]. In MRL/lpr mice, tIK treatment reduces renal damage, T cell and macrophage infiltration, IFN-gamma and IL-2 production, and anti-DNA antibody titers, establishing that IK modulates autoimmune pathology through class II MHC-dependent suppression of immune activation [PMID:17075801]. Beyond its role as an immunomodulatory cytokine, no further molecular mechanism of CIITA suppression or receptor engagement has been characterized in the available corpus.","teleology":[{"year":1994,"claim":"Established IK as a novel secreted cytokine by purifying it, cloning its cDNA, and showing transfection-driven secretion of a 19 kDa protein that neutralizably inhibits IFN-gamma-induced HLA class II expression — defining a previously unknown immunomodulatory factor with no homology to known cytokines.","evidence":"protein purification, monoclonal antibody neutralization, cDNA cloning/sequencing, COS cell transfection, and HLA-DR suppression assay in Colo 205 cells","pmids":["7970704"],"confidence":"High","gaps":["no receptor or direct molecular target identified","mechanism of HLA class II suppression not resolved at this stage","physiological source and regulation of secretion unknown"]},{"year":2006,"claim":"Defined the downstream mechanism and therapeutic relevance by showing a truncated IK (tIK) suppresses class II MHC via reduced CIITA expression and attenuates autoimmune renal pathology in lupus-prone mice.","evidence":"engineered truncated IK protein, transfection of fibroblastoid cells, subcutaneous injection into MRL/lpr mice, histology, flow cytometry for MHC, and ELISA for cytokines/antibodies","pmids":["17075801"],"confidence":"Medium","gaps":["molecular link between secreted IK and CIITA downregulation not defined","no IK receptor identified to explain signal transduction","single-lab in vivo model"]},{"year":2008,"claim":"Implicated IK in cardiac muscle contractility, distinct from its cytokine role, via loss-of-function in a developmental model linked to a dilated cardiomyopathy locus.","evidence":"morpholino antisense knockdown of the zebrafish IK ortholog with cardiac contractility phenotyping, alongside human genetic association","pmids":["19064678"],"confidence":"Low","gaps":["single zebrafish morpholino without mammalian validation or rescue","no mechanistic pathway connecting IK to contractile function","relationship to the cytokine/MHC role unestablished"]},{"year":null,"claim":"How secreted IK molecularly engages target cells to lower CIITA, and whether its reported cardiac function reflects a distinct mechanism, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["no IK receptor or direct binding partner identified","biochemical mechanism of CIITA suppression undefined","cardiac role not reconciled with immunomodulatory role"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13123","full_name":"Protein Red","aliases":["Cytokine IK","IK factor","Protein RER"],"length_aa":557,"mass_kda":65.6,"function":"Involved in pre-mRNA splicing as a component of the spliceosome (PubMed:28781166). Auxiliary spliceosomal protein that regulates selection of alternative splice sites in a small set of target pre-mRNA species (Probable). Required for normal mitotic cell cycle progression (PubMed:22351768, PubMed:24252166). Recruits MAD1L1 and MAD2L1 to kinetochores, and is required to trigger the spindle assembly checkpoint (PubMed:22351768). Required for normal accumulation of SMU1 (PubMed:24945353) (Microbial infection) Required, together with SMU1, for normal splicing of influenza A virus NS1 pre-mRNA, which is required for the production of the exportin NS2 and for the production of influenza A virus particles. Not required for the production of VSV virus particles","subcellular_location":"Nucleus; Nucleus, nucleoplasm; Chromosome; Cytoplasm, cytoskeleton, spindle pole","url":"https://www.uniprot.org/uniprotkb/Q13123/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/IK","classification":"Common Essential","n_dependent_lines":1206,"n_total_lines":1208,"dependency_fraction":0.9983443708609272},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PRPF4B","stoichiometry":4.0},{"gene":"RAB8B","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2},{"gene":"SNRPB","stoichiometry":0.2},{"gene":"SNRPC","stoichiometry":0.2},{"gene":"SNRPF","stoichiometry":0.2},{"gene":"TOP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IK","total_profiled":1310},"omim":[{"mim_id":"620104","title":"AMELOGENESIS IMPERFECTA, TYPE IK; AI1K","url":"https://www.omim.org/entry/620104"},{"mim_id":"619628","title":"AFTIPHILIN; AFTPH","url":"https://www.omim.org/entry/619628"},{"mim_id":"619313","title":"IMMUNODEFICIENCY 80 WITH OR WITHOUT CONGENITAL CARDIOMYOPATHY; IMD80","url":"https://www.omim.org/entry/619313"},{"mim_id":"619183","title":"PROTEASOME-ASSOCIATED AUTOINFLAMMATORY SYNDROME 4; PRAAS4","url":"https://www.omim.org/entry/619183"},{"mim_id":"619070","title":"LETM1 DOMAIN-CONTAINING PROTEIN 1; LETMD1","url":"https://www.omim.org/entry/619070"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nuclear speckles","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IK"},"hgnc":{"alias_symbol":["RED","RER"],"prev_symbol":[]},"alphafold":{"accession":"Q13123","domains":[{"cath_id":"-","chopping":"230-273","consensus_level":"medium","plddt":79.1416,"start":230,"end":273},{"cath_id":"1.10.287","chopping":"77-113","consensus_level":"medium","plddt":84.7638,"start":77,"end":113},{"cath_id":"1.20.5","chopping":"333-378","consensus_level":"medium","plddt":89.9289,"start":333,"end":378}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13123","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13123-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13123-F1-predicted_aligned_error_v6.png","plddt_mean":68.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IK","jax_strain_url":"https://www.jax.org/strain/search?query=IK"},"sequence":{"accession":"Q13123","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13123.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13123/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13123"}},"corpus_meta":[{"pmid":"8261516","id":"PMC_8261516","title":"Hypermutability and mismatch repair deficiency in RER+ tumor cells.","date":"1993","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/8261516","citation_count":1012,"is_preprint":false},{"pmid":"16330682","id":"PMC_16330682","title":"The G protein-gated potassium current I(K,ACh) is constitutively active in patients with chronic atrial fibrillation.","date":"2005","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/16330682","citation_count":385,"is_preprint":false},{"pmid":"8294506","id":"PMC_8294506","title":"Characterization of the budding compartment of mouse hepatitis virus: evidence that transport from the RER to the Golgi complex requires only one vesicular transport step.","date":"1994","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/8294506","citation_count":279,"is_preprint":false},{"pmid":"11714649","id":"PMC_11714649","title":"Molecular basis of downregulation of G-protein-coupled inward rectifying K(+) current (I(K,ACh) in chronic human atrial fibrillation: decrease in GIRK4 mRNA correlates with reduced I(K,ACh) and muscarinic receptor-mediated shortening of action potentials.","date":"2001","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/11714649","citation_count":265,"is_preprint":false},{"pmid":"20362275","id":"PMC_20362275","title":"Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta.","date":"2010","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20362275","citation_count":227,"is_preprint":false},{"pmid":"9626054","id":"PMC_9626054","title":"Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology. Poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+.","date":"1998","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/9626054","citation_count":209,"is_preprint":false},{"pmid":"10545133","id":"PMC_10545133","title":"Developmental expression of the potassium current IK,n contributes to maturation of mouse outer hair cells.","date":"1999","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10545133","citation_count":183,"is_preprint":false},{"pmid":"15471565","id":"PMC_15471565","title":"Activation of human IK and SK Ca2+ -activated K+ channels by NS309 (6,7-dichloro-1H-indole-2,3-dione 3-oxime).","date":"2004","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/15471565","citation_count":171,"is_preprint":false},{"pmid":"2452034","id":"PMC_2452034","title":"Quinidine delays IK activation in guinea pig ventricular myocytes.","date":"1988","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/2452034","citation_count":140,"is_preprint":false},{"pmid":"23602968","id":"PMC_23602968","title":"A molecular ensemble in the rER for procollagen maturation.","date":"2013","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/23602968","citation_count":139,"is_preprint":false},{"pmid":"8406995","id":"PMC_8406995","title":"Production of monoclonal antibodies to human estrogen-receptor protein (ER) using recombinant ER (RER).","date":"1993","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/8406995","citation_count":139,"is_preprint":false},{"pmid":"6162651","id":"PMC_6162651","title":"Distinct epitopes of Ik gene products identified by monoclonal antibodies.","date":"1980","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/6162651","citation_count":128,"is_preprint":false},{"pmid":"12451110","id":"PMC_12451110","title":"Delayed rectifier K+ currents, IK, are encoded by Kv2 alpha-subunits and regulate tonic firing in mammalian sympathetic neurons.","date":"2002","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/12451110","citation_count":125,"is_preprint":false},{"pmid":"9104602","id":"PMC_9104602","title":"Effects of a cognition-enhancer, linopirdine (DuP 996), on M-type potassium currents (IK(M)) and some other voltage- and ligand-gated membrane currents in rat sympathetic neurons.","date":"1997","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/9104602","citation_count":120,"is_preprint":false},{"pmid":"17362895","id":"PMC_17362895","title":"Differential phosphorylation-dependent regulation of constitutively active and muscarinic receptor-activated IK,ACh channels in patients with chronic atrial fibrillation.","date":"2007","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/17362895","citation_count":109,"is_preprint":false},{"pmid":"9000147","id":"PMC_9000147","title":"Inverse correlation between RER+ status and p53 mutation in colorectal cancer cell lines.","date":"1996","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9000147","citation_count":108,"is_preprint":false},{"pmid":"9715273","id":"PMC_9715273","title":"Chromosome number and structure both are markedly stable in RER colorectal cancers and are not destabilized by mutation of p53.","date":"1998","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9715273","citation_count":102,"is_preprint":false},{"pmid":"18536759","id":"PMC_18536759","title":"Pathology-specific effects of the IKur/Ito/IK,ACh blocker AVE0118 on ion channels in human chronic atrial fibrillation.","date":"2008","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/18536759","citation_count":99,"is_preprint":false},{"pmid":"10357799","id":"PMC_10357799","title":"Familial gastric cancer: clinicopathological characteristics, RER phenotype and germline p53 and E-cadherin mutations.","date":"1999","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/10357799","citation_count":97,"is_preprint":false},{"pmid":"9071575","id":"PMC_9071575","title":"Mutational analysis of MLH1 and MSH2 in 25 prospectively-acquired RER+ endometrial cancers.","date":"1997","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/9071575","citation_count":94,"is_preprint":false},{"pmid":"8997308","id":"PMC_8997308","title":"IK of rabbit ventricle is composed of two currents: evidence for IKs.","date":"1996","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/8997308","citation_count":90,"is_preprint":false},{"pmid":"15140747","id":"PMC_15140747","title":"Overexpression of human KCNA5 increases IK V and enhances apoptosis.","date":"2004","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15140747","citation_count":86,"is_preprint":false},{"pmid":"19788711","id":"PMC_19788711","title":"Lactobacillus reuteri ingestion and IK(Ca) channel blockade have similar effects on rat colon motility and myenteric neurones.","date":"2009","source":"Neurogastroenterology and motility","url":"https://pubmed.ncbi.nlm.nih.gov/19788711","citation_count":80,"is_preprint":false},{"pmid":"19064678","id":"PMC_19064678","title":"HBEGF, SRA1, and IK: Three cosegregating genes as determinants of cardiomyopathy.","date":"2008","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/19064678","citation_count":79,"is_preprint":false},{"pmid":"10908314","id":"PMC_10908314","title":"Evidence for Edg-3 receptor-mediated activation of I(K.ACh) by sphingosine-1-phosphate in human atrial cardiomyocytes.","date":"2000","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/10908314","citation_count":76,"is_preprint":false},{"pmid":"12388088","id":"PMC_12388088","title":"IK channels are involved in the regulatory volume decrease in human epithelial cells.","date":"2002","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12388088","citation_count":74,"is_preprint":false},{"pmid":"21677177","id":"PMC_21677177","title":"Dynamic interaction of Ih and IK-LVA during trains of synaptic potentials in principal neurons of the medial superior olive.","date":"2011","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21677177","citation_count":71,"is_preprint":false},{"pmid":"25638716","id":"PMC_25638716","title":"Microsporidia and Cryptosporidium in horses and donkeys in Algeria: detection of a novel Cryptosporidium hominis subtype family (Ik) in a horse.","date":"2015","source":"Veterinary parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/25638716","citation_count":70,"is_preprint":false},{"pmid":"9064651","id":"PMC_9064651","title":"Reversible inhibition of IK, IAHP, Ih and ICa currents by internally applied gluconate in rat hippocampal pyramidal neurones.","date":"1997","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/9064651","citation_count":68,"is_preprint":false},{"pmid":"10652255","id":"PMC_10652255","title":"Dictyostelium myosin IK is involved in the maintenance of cortical tension and affects motility and phagocytosis.","date":"2000","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/10652255","citation_count":66,"is_preprint":false},{"pmid":"17610583","id":"PMC_17610583","title":"IL-1beta inhibits IK and increases [Ca2+]i in the carotid body glomus cells and increases carotid sinus nerve firings in the rat.","date":"2007","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/17610583","citation_count":64,"is_preprint":false},{"pmid":"7691849","id":"PMC_7691849","title":"cis-Golgi resident proteins and O-glycans are abnormally compartmentalized in the RER of colon cancer cells.","date":"1993","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/7691849","citation_count":62,"is_preprint":false},{"pmid":"14973782","id":"PMC_14973782","title":"Congenital disorder of glycosylation type Ik (CDG-Ik): a defect of mannosyltransferase I.","date":"2004","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14973782","citation_count":62,"is_preprint":false},{"pmid":"14973778","id":"PMC_14973778","title":"Deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase causes congenital disorder of glycosylation type Ik.","date":"2004","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14973778","citation_count":62,"is_preprint":false},{"pmid":"8640835","id":"PMC_8640835","title":"Analysis of replication error (RER+) phenotypes in cervical carcinoma.","date":"1996","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/8640835","citation_count":60,"is_preprint":false},{"pmid":"11741516","id":"PMC_11741516","title":"Inhibitory effects of berberine on IK1, IK, and HERG channels of cardiac myocytes.","date":"2001","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/11741516","citation_count":59,"is_preprint":false},{"pmid":"22992678","id":"PMC_22992678","title":"Differential role of IK and BK potassium channels as mediators of intrinsic and extrinsic apoptotic cell death.","date":"2012","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/22992678","citation_count":57,"is_preprint":false},{"pmid":"22045927","id":"PMC_22045927","title":"Genetic polymorphisms in carnitine palmitoyltransferase 1A gene are associated with variation in body composition and fasting lipid traits in Yup'ik Eskimos.","date":"2011","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/22045927","citation_count":56,"is_preprint":false},{"pmid":"1662903","id":"PMC_1662903","title":"Distinct voltage-dependent regulation of a heart-delayed IK by protein kinases A and C.","date":"1991","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/1662903","citation_count":53,"is_preprint":false},{"pmid":"32463112","id":"PMC_32463112","title":"Mechanisms underlying selective coupling of endothelial Ca2+ signals with eNOS vs. IK/SK channels in systemic and pulmonary arteries.","date":"2020","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32463112","citation_count":52,"is_preprint":false},{"pmid":"8576239","id":"PMC_8576239","title":"RER, an evolutionarily conserved sequence upstream of the rhodopsin gene, has enhancer activity.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8576239","citation_count":52,"is_preprint":false},{"pmid":"7864185","id":"PMC_7864185","title":"Regional differences in IK density in canine left ventricle: role of IK,s in electrical heterogeneity.","date":"1995","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/7864185","citation_count":49,"is_preprint":false},{"pmid":"16441566","id":"PMC_16441566","title":"The distribution of intermediate-conductance, calcium-activated, potassium (IK) channels in epithelial cells.","date":"2006","source":"Journal of anatomy","url":"https://pubmed.ncbi.nlm.nih.gov/16441566","citation_count":48,"is_preprint":false},{"pmid":"10568794","id":"PMC_10568794","title":"The fibroblast intermediate conductance K(Ca) channel, FIK, as a prototype for the cell growth regulatory function of the IK channel family.","date":"1999","source":"The Journal of membrane biology","url":"https://pubmed.ncbi.nlm.nih.gov/10568794","citation_count":48,"is_preprint":false},{"pmid":"26041939","id":"PMC_26041939","title":"Ca2+-Activated IK K+ Channel Blockade Radiosensitizes Glioblastoma Cells.","date":"2015","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/26041939","citation_count":47,"is_preprint":false},{"pmid":"27752766","id":"PMC_27752766","title":"KCa3.1 (IK) modulates pancreatic cancer cell migration, invasion and proliferation: anomalous effects on TRAM-34.","date":"2016","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27752766","citation_count":46,"is_preprint":false},{"pmid":"2260712","id":"PMC_2260712","title":"Lanthanum blocks a specific component of IK and screens membrane surface change in cardiac cells.","date":"1990","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/2260712","citation_count":46,"is_preprint":false},{"pmid":"24477300","id":"PMC_24477300","title":"DNA methylation patterns are associated with n-3 fatty acid intake in Yup'ik people.","date":"2014","source":"The Journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/24477300","citation_count":45,"is_preprint":false},{"pmid":"10662889","id":"PMC_10662889","title":"Modulation of delayed rectifier potassium current, iK, by isoprenaline in rabbit isolated pacemaker cells.","date":"2000","source":"Experimental physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10662889","citation_count":44,"is_preprint":false},{"pmid":"27180889","id":"PMC_27180889","title":"Atrial Fibrillation-Mediated Upregulation of miR-30d Regulates Myocardial Electrical Remodeling of the G-Protein-Gated K(+) Channel, IK.ACh.","date":"2016","source":"Circulation journal : official journal of the Japanese Circulation Society","url":"https://pubmed.ncbi.nlm.nih.gov/27180889","citation_count":44,"is_preprint":false},{"pmid":"8389083","id":"PMC_8389083","title":"The RER-localized rotavirus intracellular receptor: a truncated purified soluble form is multivalent and binds virus particles.","date":"1993","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/8389083","citation_count":43,"is_preprint":false},{"pmid":"19059527","id":"PMC_19059527","title":"Relationships between plasma adiponectin and body fat distribution, insulin sensitivity, and plasma lipoproteins in Alaskan Yup'ik Eskimos: the Center for Alaska Native Health Research study.","date":"2009","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/19059527","citation_count":43,"is_preprint":false},{"pmid":"9223288","id":"PMC_9223288","title":"Targeted inactivation of alphai2 or alphai3 disrupts activation of the cardiac muscarinic K+ channel, IK+Ach, in intact cells.","date":"1997","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9223288","citation_count":42,"is_preprint":false},{"pmid":"9379409","id":"PMC_9379409","title":"Histamine H1 receptor activation blocks two classes of potassium current, IK(rest) and IAHP, to excite ferret vagal afferents.","date":"1997","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/9379409","citation_count":41,"is_preprint":false},{"pmid":"10393806","id":"PMC_10393806","title":"The major olive pollen allergen (Ole e I) shows both gametophytic and sporophytic expression during anther development, and its synthesis and storage takes place in the RER.","date":"1999","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/10393806","citation_count":40,"is_preprint":false},{"pmid":"3174403","id":"PMC_3174403","title":"Angiotensin II increases Isi and blocks IK in single aortic cell of rabbit.","date":"1988","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/3174403","citation_count":39,"is_preprint":false},{"pmid":"35666806","id":"PMC_35666806","title":"Discovery and Characterization of a Novel Aryl Hydrocarbon Receptor Inhibitor, IK-175, and Its Inhibitory Activity on Tumor Immune Suppression.","date":"2022","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/35666806","citation_count":38,"is_preprint":false},{"pmid":"14527939","id":"PMC_14527939","title":"Selective elimination of I(K,slow1) in mouse ventricular myocytes expressing a dominant negative Kv1.5alpha subunit.","date":"2003","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/14527939","citation_count":37,"is_preprint":false},{"pmid":"10640448","id":"PMC_10640448","title":"Localization of K(+) channels in the tubules of cardiomyocytes as suggested by the parallel decay of membrane capacitance, IK(1) and IK(ATP) during culture and by delayed IK(1) response to barium.","date":"1999","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/10640448","citation_count":36,"is_preprint":false},{"pmid":"7970704","id":"PMC_7970704","title":"A new cytokine (IK) down-regulating HLA class II: monoclonal antibodies, cloning and chromosome localization.","date":"1994","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/7970704","citation_count":36,"is_preprint":false},{"pmid":"11514288","id":"PMC_11514288","title":"Characterization of mice with a combined suppression of I(to) and I(K,slow).","date":"2001","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/11514288","citation_count":36,"is_preprint":false},{"pmid":"22592639","id":"PMC_22592639","title":"SK but not IK channels regulate human detrusor smooth muscle spontaneous and nerve-evoked contractions.","date":"2012","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/22592639","citation_count":35,"is_preprint":false},{"pmid":"7992198","id":"PMC_7992198","title":"Dopamine neuron membrane physiology: characterization of the transient outward current (IA) and demonstration of a common signal transduction pathway for IA and IK.","date":"1994","source":"Synapse (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/7992198","citation_count":35,"is_preprint":false},{"pmid":"20200225","id":"PMC_20200225","title":"A myosin IK-Abp1-PakB circuit acts as a switch to regulate phagocytosis efficiency.","date":"2010","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/20200225","citation_count":35,"is_preprint":false},{"pmid":"17075801","id":"PMC_17075801","title":"IK cytokine ameliorates the progression of lupus nephritis in MRL/lpr mice.","date":"2006","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/17075801","citation_count":33,"is_preprint":false},{"pmid":"26064452","id":"PMC_26064452","title":"Functional coupling of TRPV4, IK, and SK channels contributes to Ca(2+)-dependent endothelial injury in rodent lung.","date":"2015","source":"Pulmonary circulation","url":"https://pubmed.ncbi.nlm.nih.gov/26064452","citation_count":33,"is_preprint":false},{"pmid":"19282171","id":"PMC_19282171","title":"Inhibitors of potassium channels KV1.3 and IK-1 as immunosuppressants.","date":"2009","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/19282171","citation_count":33,"is_preprint":false},{"pmid":"8160815","id":"PMC_8160815","title":"Metabolic inhibition of ICa,L and IK differs in feline left ventricular hypertrophy.","date":"1994","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/8160815","citation_count":31,"is_preprint":false},{"pmid":"20679665","id":"PMC_20679665","title":"Guanosine diphosphate-mannose:GlcNAc2-PP-dolichol mannosyltransferase deficiency (congenital disorders of glycosylation type Ik): five new patients and seven novel mutations.","date":"2010","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20679665","citation_count":31,"is_preprint":false},{"pmid":"24931203","id":"PMC_24931203","title":"Constitutive activity of the acetylcholine-activated potassium current IK,ACh in cardiomyocytes.","date":"2014","source":"Advances in pharmacology (San Diego, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/24931203","citation_count":30,"is_preprint":false},{"pmid":"14684365","id":"PMC_14684365","title":"Attenuation of I(K,slow1) and I(K,slow2) in Kv1/Kv2DN mice prolongs APD and QT intervals but does not suppress spontaneous or inducible arrhythmias.","date":"2004","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/14684365","citation_count":30,"is_preprint":false},{"pmid":"17229825","id":"PMC_17229825","title":"Effects of compounds that influence IK (KCNN4) channels on afterhyperpolarizing potentials, and determination of IK channel sequence, in guinea pig enteric neurons.","date":"2007","source":"Journal of neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/17229825","citation_count":29,"is_preprint":false},{"pmid":"32436234","id":"PMC_32436234","title":"Effect of selective IK,ACh inhibition by XAF-1407 in an equine model of tachypacing-induced persistent atrial fibrillation.","date":"2020","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32436234","citation_count":28,"is_preprint":false},{"pmid":"9498272","id":"PMC_9498272","title":"RER phenotype and its associated mutations in familial gastric cancer.","date":"1998","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/9498272","citation_count":27,"is_preprint":false},{"pmid":"9591632","id":"PMC_9591632","title":"A beta-catenin mutation in a sporadic colorectal tumor of the RER phenotype and absence of beta-catenin germline mutations in FAP patients.","date":"1998","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/9591632","citation_count":27,"is_preprint":false},{"pmid":"26661839","id":"PMC_26661839","title":"Genetics, Diet, and Season Are Associated with Serum 25-Hydroxycholecalciferol Concentration in a Yup'ik Study Population from Southwestern Alaska.","date":"2015","source":"The Journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/26661839","citation_count":27,"is_preprint":false},{"pmid":"10742299","id":"PMC_10742299","title":"Compounds that block both intermediate-conductance (IK(Ca)) and small-conductance (SK(Ca)) calcium-activated potassium channels.","date":"2000","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/10742299","citation_count":27,"is_preprint":false},{"pmid":"2812502","id":"PMC_2812502","title":"Carbachol reduces IK,baclofen, but not IK,GABA in guinea pig hippocampal slices.","date":"1989","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/2812502","citation_count":26,"is_preprint":false},{"pmid":"11779563","id":"PMC_11779563","title":"Calmodulin antagonists do not inhibit IK(Ca) channels of human erythrocytes.","date":"2002","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/11779563","citation_count":26,"is_preprint":false},{"pmid":"7892108","id":"PMC_7892108","title":"Activation of nucleotide receptors inhibits M-type K current [IK(M)] in neuroblastoma x glioma hybrid cells.","date":"1994","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/7892108","citation_count":26,"is_preprint":false},{"pmid":"1432069","id":"PMC_1432069","title":"Modulation of IK,Ca by phorbol ester-mediated activation of PKC in pleural sensory neurons of Aplysia.","date":"1992","source":"Journal of neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/1432069","citation_count":25,"is_preprint":false},{"pmid":"10370060","id":"PMC_10370060","title":"A Na+-activated K+ current (IK,Na) is present in guinea-pig but not rat ventricular myocytes.","date":"1999","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10370060","citation_count":25,"is_preprint":false},{"pmid":"26936968","id":"PMC_26936968","title":"Mechanism of chitosan recognition by CBM32 carbohydrate-binding modules from a Paenibacillus sp. IK-5 chitosanase/glucanase.","date":"2016","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/26936968","citation_count":25,"is_preprint":false},{"pmid":"24598880","id":"PMC_24598880","title":"A stable isotope biomarker of marine food intake captures associations between n-3 fatty acid intake and chronic disease risk in a Yup'ik study population, and detects new associations with blood pressure and adiponectin.","date":"2014","source":"The Journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/24598880","citation_count":24,"is_preprint":false},{"pmid":"29290419","id":"PMC_29290419","title":"Muscarinic type-1 receptors contribute to IK,ACh in human atrial cardiomyocytes and are upregulated in patients with chronic atrial fibrillation.","date":"2017","source":"International journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/29290419","citation_count":24,"is_preprint":false},{"pmid":"15361209","id":"PMC_15361209","title":"Molecular differences between RER+ and RER- sporadic endometrial carcinomas in a large population-based series.","date":"2004","source":"International journal of gynecological cancer : official journal of the International Gynecological Cancer Society","url":"https://pubmed.ncbi.nlm.nih.gov/15361209","citation_count":23,"is_preprint":false},{"pmid":"20501432","id":"PMC_20501432","title":"Identification and functional characterization of the intermediate-conductance Ca(2+)-activated K(+) channel (IK-1) in biliary epithelium.","date":"2009","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/20501432","citation_count":23,"is_preprint":false},{"pmid":"33631195","id":"PMC_33631195","title":"Type I and type V procollagen triple helix uses different subsets of the molecular ensemble for lysine posttranslational modifications in the rER.","date":"2021","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33631195","citation_count":23,"is_preprint":false},{"pmid":"25884514","id":"PMC_25884514","title":"The transcription factors Ik-1 and MZF1 downregulate IGF-IR expression in NPM-ALK⁺ T-cell lymphoma.","date":"2015","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25884514","citation_count":21,"is_preprint":false},{"pmid":"28962702","id":"PMC_28962702","title":"Involvement of dysregulated IKCa and SKCa channels in preeclampsia.","date":"2017","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/28962702","citation_count":21,"is_preprint":false},{"pmid":"10451700","id":"PMC_10451700","title":"A somatic BRCA2 mutation in RER+ endometrial carcinomas that specifically deletes the amino-terminal transactivation domain.","date":"1999","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10451700","citation_count":21,"is_preprint":false},{"pmid":"8001769","id":"PMC_8001769","title":"Characterization of the aac(6')-Ik gene of Acinetobacter sp. 6.","date":"1994","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/8001769","citation_count":21,"is_preprint":false},{"pmid":"10679912","id":"PMC_10679912","title":"Genomic FHIT analysis in RER+ and RER- adenocarcinomas of the pancreas.","date":"2000","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10679912","citation_count":20,"is_preprint":false},{"pmid":"8392035","id":"PMC_8392035","title":"Autocrine growth mechanism by transforming growth factor (TGF)-beta 1 and TGF-beta 1-receptor regulation by epidermal growth factor in a human endometrial cancer cell line IK-90.","date":"1993","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/8392035","citation_count":19,"is_preprint":false},{"pmid":"25772781","id":"PMC_25772781","title":"Linkage and association analysis of obesity traits reveals novel loci and interactions with dietary n-3 fatty acids in an Alaska Native (Yup'ik) population.","date":"2015","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/25772781","citation_count":19,"is_preprint":false},{"pmid":"15233935","id":"PMC_15233935","title":"Intermediate conductance potassium (IK) channels occur in human enteric neurons.","date":"2004","source":"Autonomic neuroscience : basic & clinical","url":"https://pubmed.ncbi.nlm.nih.gov/15233935","citation_count":18,"is_preprint":false},{"pmid":"7500156","id":"PMC_7500156","title":"Evidence for a contribution of ICa to serotonergic modulation of IK,Ca in Hermissenda photoreceptors.","date":"1995","source":"Journal of neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/7500156","citation_count":18,"is_preprint":false},{"pmid":"9152858","id":"PMC_9152858","title":"Acetylcholine modulates I(f) and IK(ACh) via different pathways in rabbit sino-atrial node cells.","date":"1997","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/9152858","citation_count":18,"is_preprint":false},{"pmid":"17722068","id":"PMC_17722068","title":"Vertebrate rod photoreceptors express both BK and IK calcium-activated potassium channels, but only BK channels are involved in receptor potential regulation.","date":"2008","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/17722068","citation_count":18,"is_preprint":false},{"pmid":"24112421","id":"PMC_24112421","title":"CDKAL1 and HHEX are associated with type 2 diabetes-related traits among Yup'ik people.","date":"2013","source":"Journal of diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/24112421","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54601,"output_tokens":1405,"usd":0.092439,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7613,"output_tokens":1574,"usd":0.038707,"stage2_stop_reason":"end_turn"},"total_usd":0.131146,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers about the canonical human IK protein (also known as RER). Based on the corpus context, the gene IK/RER encodes a cytokine that inhibits HLA class II expression. Let me identify the relevant papers.\n\nPaper [60] is the key paper: \"A new cytokine (IK) down-regulating HLA class II: monoclonal antibodies, cloning and chromosome localization\" (Krief et al., 1994, Oncogene, PMID:7970704). This directly describes the IK cytokine/protein.\n\nPaper [65] describes IK cytokine in lupus: \"IK cytokine ameliorates the progression of lupus nephritis in MRL/lpr mice\" (PMID:17075801).\n\nPaper [24] mentions IK as one of three cosegregating genes associated with cardiomyopathy (PMID:19064678).\n\nPaper [89] describes \"Ik-1\" but this refers to Ikaros isoform 1 (IKZF1), not the IK cytokine gene — this is a collision. Skip.\n\nMost other papers are about potassium currents (IK as abbreviation for potassium current), RER as replication error repair, or other unrelated topics. These are not about the IK gene/protein.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"IK encodes a 19 kDa cytokine secreted by the leukemic cell line K562 and several cancer cells that inhibits IFN-gamma-induced HLA class II antigen expression. The gene maps to chromosome 2p15-p14, its mRNA is approximately 2.1 kb, and transient transfection of the IK cDNA into COS cells induces secretion of a biologically active 19 kDa protein recognized by a blocking monoclonal antibody. The nucleotide sequence showed no homology to known cytokines at the time.\",\n      \"method\": \"Protein purification, monoclonal antibody production, cDNA cloning and sequencing, transient transfection of COS cells, Western blot, chromosome mapping, functional inhibition assay (IFN-gamma-induced HLA-DR suppression in Colo 205 cells)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods in a single study: purification, cloning, sequencing, functional rescue by transient transfection, and antibody-mediated neutralization of biological activity\",\n      \"pmids\": [\"7970704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A truncated IK analog (tIK), translated from methionine at position 316, acts as a secretory protein and reduces IFN-gamma-induced HLA class II MHC expression through decreased expression of the class II MHC transcription activator (CIITA). In MRL/lpr mice, tIK treatment significantly reduced renal damage, decreased macrophage and T cell infiltration in kidneys, reduced IFN-gamma and IL-2 production, and decreased anti-DNA antibodies and circulating immune complexes, demonstrating that IK cytokine modulates autoimmune pathology via suppression of class II MHC-dependent immune activation.\",\n      \"method\": \"Truncated IK protein engineering, transfection into fibroblastoid cell line, subcutaneous injection into MRL/lpr mice, histological analysis of kidneys, flow cytometry for class II MHC expression on B cells and monocytes, ELISA for cytokines and antibodies\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss/gain-of-function in vivo with multiple defined readouts (renal pathology, immune infiltration, cytokine levels, antibody titers, MHC expression) from a single lab\",\n      \"pmids\": [\"17075801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Morpholino-mediated knockdown of the zebrafish ortholog of IK in zebrafish embryos results in myocardial contractile dysfunction, establishing that IK has a functional role in cardiac muscle contractility. This was demonstrated in a genetic epistasis/loss-of-function screen alongside HBEGF and SRA1 within a 600-kb linkage disequilibrium block on 5q31.2-3 associated with dilated cardiomyopathy.\",\n      \"method\": \"Morpholino antisense knockdown in zebrafish, cardiac contractility phenotype assessment, genetic association analysis in human populations\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single zebrafish morpholino knockdown experiment, phenotype reported but no mechanistic pathway placement beyond contractile dysfunction; single lab, no mammalian ortholog validation\",\n      \"pmids\": [\"19064678\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IK (also called RER) encodes a secreted 19 kDa cytokine that inhibits IFN-gamma-induced HLA class II MHC antigen expression by suppressing class II MHC transcription activator (CIITA) levels; a truncated form of IK translated from an internal methionine is sufficient for secretion and biological activity, and IK has been shown to reduce autoimmune pathology in mouse models of lupus nephritis through class II MHC-dependent suppression of T cell and macrophage infiltration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IK (also called RER) encodes a 19 kDa cytokine secreted by leukemic and cancer cell lines that inhibits IFN-gamma-induced HLA class II MHC antigen expression, identified through protein purification, cDNA cloning, and antibody-mediated neutralization of its biological activity [#0]. Mechanistically, IK suppresses class II MHC expression by decreasing levels of the class II MHC transcription activator (CIITA), and a truncated form translated from an internal methionine (tIK) retains both secretion and this inhibitory activity [#1]. In MRL/lpr mice, tIK treatment reduces renal damage, T cell and macrophage infiltration, IFN-gamma and IL-2 production, and anti-DNA antibody titers, establishing that IK modulates autoimmune pathology through class II MHC-dependent suppression of immune activation [#1]. Beyond its role as an immunomodulatory cytokine, no further molecular mechanism of CIITA suppression or receptor engagement has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established IK as a novel secreted cytokine by purifying it, cloning its cDNA, and showing transfection-driven secretion of a 19 kDa protein that neutralizably inhibits IFN-gamma-induced HLA class II expression — defining a previously unknown immunomodulatory factor with no homology to known cytokines.\",\n      \"evidence\": \"protein purification, monoclonal antibody neutralization, cDNA cloning/sequencing, COS cell transfection, and HLA-DR suppression assay in Colo 205 cells\",\n      \"pmids\": [\"7970704\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"no receptor or direct molecular target identified\",\n        \"mechanism of HLA class II suppression not resolved at this stage\",\n        \"physiological source and regulation of secretion unknown\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the downstream mechanism and therapeutic relevance by showing a truncated IK (tIK) suppresses class II MHC via reduced CIITA expression and attenuates autoimmune renal pathology in lupus-prone mice.\",\n      \"evidence\": \"engineered truncated IK protein, transfection of fibroblastoid cells, subcutaneous injection into MRL/lpr mice, histology, flow cytometry for MHC, and ELISA for cytokines/antibodies\",\n      \"pmids\": [\"17075801\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"molecular link between secreted IK and CIITA downregulation not defined\",\n        \"no IK receptor identified to explain signal transduction\",\n        \"single-lab in vivo model\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Implicated IK in cardiac muscle contractility, distinct from its cytokine role, via loss-of-function in a developmental model linked to a dilated cardiomyopathy locus.\",\n      \"evidence\": \"morpholino antisense knockdown of the zebrafish IK ortholog with cardiac contractility phenotyping, alongside human genetic association\",\n      \"pmids\": [\"19064678\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"single zebrafish morpholino without mammalian validation or rescue\",\n        \"no mechanistic pathway connecting IK to contractile function\",\n        \"relationship to the cytokine/MHC role unestablished\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How secreted IK molecularly engages target cells to lower CIITA, and whether its reported cardiac function reflects a distinct mechanism, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"no IK receptor or direct binding partner identified\",\n        \"biochemical mechanism of CIITA suppression undefined\",\n        \"cardiac role not reconciled with immunomodulatory role\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}