{"gene":"IL15RA","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1995,"finding":"Human IL-15Rα (IL15RA) binds IL-15 with ~1000-fold higher affinity than IL-2Rα binds IL-2; three differentially spliced human IL-15Rα variants all retain high-affinity IL-15 binding. The cytoplasmic domain of IL-15Rα is dispensable for mitogenic signaling, indicating the primary role of the alpha chain is to confer high-affinity ligand binding. At high IL-15 concentrations, signaling can occur through the IL-2Rβ/γ heterodimer in the absence of the alpha subunit.","method":"Binding assays with differentially spliced receptor variants; cytoplasmic domain deletion mutants; mitogenic signaling assays in cell lines","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (binding assays, deletion mutagenesis, functional signaling assays) in a highly cited foundational paper","pmids":["8530383"],"is_preprint":false},{"year":2009,"finding":"IL-15Rα expressed on CD8+ T cells can present IL-15 in cis (to the same cell), enhancing IL-15-mediated STAT5 phosphorylation, proliferation in vivo, and viability. A chimeric IL-15/IL-15Rα fusion construct autonomously enhances viability, proliferation, and cytotoxic potential of primary CD8+ T cells.","method":"RNA nucleofection of naive CD8+ T cells with IL-15Rα or IL-15/IL-15Rα fusion constructs; STAT5 phosphorylation assay; in vivo adoptive transfer proliferation assay","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (signaling assay, in vivo proliferation, viability, cytotoxicity) in a single study","pmids":["19180469"],"is_preprint":false},{"year":2014,"finding":"In triple-negative breast cancer cells expressing IL15RA but lacking IL2RB and IL2RG, IL15RA signals through a non-canonical pathway activating JAK1, STAT1, STAT2, AKT, PRAS40, and ERK1/2 (but not STAT5 or JAK2), promoting cell proliferation, migration, and blocking apoptosis in an autocrine manner. IL15RA-expressing cancer cells also activate PBMCs in a paracrine manner.","method":"RNAi-mediated knockdown of IL15RA; phosphoprotein/western blot analysis of downstream signaling; co-culture paracrine assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — RNAi loss-of-function combined with phosphoproteomic readouts, but single lab","pmids":["24980552"],"is_preprint":false},{"year":2014,"finding":"Muscle-specific deletion of IL15RA exons 2 and 3 in mice causes a pro-oxidative shift in skeletal muscle contractile phenotype, increased fatigue resistance in fast-twitch (EDL) muscles, and a twofold increase in mitochondrial genome content (COXII), alongside reduced circulating IL-15 protein levels.","method":"Cre-loxP conditional knockout (MCK-Cre); isometric contractile and fatigue assays; COXII gene copy quantification","journal":"Journal of applied physiology","confidence":"High","confidence_rationale":"Tier 2 — clean muscle-specific KO with defined functional phenotypic readouts (contractile, fatigue, mitochondrial content)","pmids":["25505029"],"is_preprint":false},{"year":2017,"finding":"IL15RA plays a cell-autonomous role in osteoblast function and bone mineralization: Il15ra-/- mice show decreased bone mineralization in vivo and in primary osteogenic cultures. Il15ra-/- osteogenic cultures exhibit a reduced RANKL/OPG mRNA ratio, indicating defective osteoblast/osteoclast coupling. shRNA silencing of Il15ra in MC3T3-E1 cells decreased ENPP1 enzymatic activity.","method":"Whole-body Il15ra knockout mouse; primary osteogenic culture mineralization assay; qPCR; shRNA knockdown; ENPP1 activity assay; transcriptome analysis","journal":"Bone","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with in vivo and in vitro orthogonal assays plus enzymatic activity readout","pmids":["28602725"],"is_preprint":false},{"year":2018,"finding":"Loss of IL15RA in mice results in higher mitochondrial content and increased cristae density in subsarcolemmal and A-band mitochondrial subpopulations of fast-twitch (EDL) skeletal muscle, associated with elevated OPA1 protein and cardiolipin levels, without changes in myosin heavy chain fiber-type distribution.","method":"Il15ra whole-body knockout; electron microscopy; immunostaining for MyHC isoforms; OPA1 and cardiolipin quantification","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — KO model with ultrastructural (EM) and biochemical orthogonal readouts","pmids":["30301784"],"is_preprint":false},{"year":2010,"finding":"IL-15RA gene expression is regulated by DNA methylation: treatment of PBMCs with the DNA methyltransferase inhibitor 5-azacitidine significantly increased IL-15RA copy number, specifically affecting alternative exon-skipping variants of the Var1 transcript (Del2, Del3, Del2,3), consistent with a CpG island in the Var1 but not Var2 regulatory region.","method":"5-azacitidine treatment; quantitative RT-PCR; transcript variant analysis","journal":"European cytokine network","confidence":"Medium","confidence_rationale":"Tier 3 — pharmacological inhibition with transcript-level readouts, single method but consistent with CpG island location","pmids":["21097393"],"is_preprint":false},{"year":2017,"finding":"CD215+ (IL-15Rα+) myeloid cells respond to IL-15 stimulation by producing IGF-1, which promotes tumor growth; blocking IGF-1 reduced the tumor-promoting effect of IL-15 in xenograft models.","method":"In vivo IL-15 injection in NSI and C57BL/6 tumor-bearing mice; flow cytometry; IGF-1 blocking antibody; xenograft tumor models","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo functional rescue/blocking experiment with defined mechanistic readout, single lab","pmids":["29255466"],"is_preprint":false},{"year":2024,"finding":"In pancreatic cancer, IL-15 secreted by pancreatic stellate cells activates the IL15RA-STAT3-GPX4/ACSL3 axis in cancer cells, simultaneously upregulating both GPX4 and ACSL3 to prevent lipid peroxidation, conferring ferroptosis resistance both in vitro and in vivo.","method":"PSC-cancer cell co-culture system; in vitro and in vivo ferroptosis assays; STAT3 pathway analysis; GPX4/ACSL3 expression assays","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo experiments with defined pathway, single lab","pmids":["39396119"],"is_preprint":false},{"year":2025,"finding":"STAT1 binds to the IL15RA promoter to enhance IL15RA mRNA expression, and METTL3-mediated RNA m6A methylation stabilizes IL15RA transcripts; IL15RA in turn promotes ccRCC metastasis via activation of the NF-κB/ZEB1 axis.","method":"Promoter binding assay (STAT1-ChIP implied); m6A methylation analysis; metastasis assays; NF-κB/ZEB1 pathway analysis in ccRCC cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — mechanistic pathway dissection with upstream regulators identified, but single lab with limited methodological detail in abstract","pmids":["41168330"],"is_preprint":false},{"year":2020,"finding":"IL-15 stimulation of cartilage explants significantly increased release of MMP-1 and MMP-3, demonstrating that IL-15Rα-expressing chondrocytes respond to IL-15 by upregulating matrix-degrading proteases.","method":"Ex vivo cartilage explant culture with IL-15; MMP-1 and MMP-3 release assay; immunohistochemistry for IL-15Rα in chondrocytes","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — ex vivo functional assay with defined protease output, but limited mechanistic depth","pmids":["32793194"],"is_preprint":false}],"current_model":"IL15RA encodes the high-affinity private alpha subunit of the IL-15 receptor that binds IL-15 with extremely high affinity (its cytoplasmic domain is dispensable for signaling); it can present IL-15 in trans to neighboring cells or in cis to the same cell (e.g., on CD8+ T cells), activating downstream JAK/STAT5, JAK1/STAT1/STAT2, AKT, and ERK signaling depending on cellular context; in cancer cells lacking IL-2Rβ/γ it drives a non-canonical JAK1-STAT1/2-AKT-ERK pathway, and in pancreatic cancer activates a STAT3-GPX4/ACSL3 ferroptosis-resistance axis; in skeletal muscle and bone, IL15RA plays cell-autonomous roles in regulating mitochondrial ultrastructure, oxidative metabolism, and osteoblast-driven bone mineralization and osteoclast coupling."},"narrative":{"teleology":[{"year":1995,"claim":"Establishing that IL15RA is the high-affinity ligand-binding subunit of the IL-15 receptor — with an affinity far exceeding IL-2Rα for IL-2 — and that its cytoplasmic domain is dispensable for signaling resolved the fundamental question of how IL-15 specificity is encoded within the shared IL-2/IL-15 receptor system.","evidence":"Binding assays with spliced receptor variants, cytoplasmic domain deletion mutants, and mitogenic signaling assays in cell lines","pmids":["8530383"],"confidence":"High","gaps":["Structural basis of the ~1000-fold affinity difference unresolved","Whether IL15RA has signaling-independent functions not addressed","Physiological cell types requiring alpha chain versus beta/gamma-only signaling not defined"]},{"year":2009,"claim":"Demonstrating that IL15RA on CD8+ T cells can present IL-15 in cis — not only in trans from accessory cells — expanded the receptor's functional repertoire beyond a simple antigen-presenting-cell-to-T-cell relay and showed autonomous enhancement of T cell proliferation and cytotoxicity.","evidence":"RNA nucleofection of IL-15Rα or IL-15/IL-15Rα fusion constructs into naive CD8+ T cells; STAT5 phosphorylation and in vivo adoptive transfer proliferation assays","pmids":["19180469"],"confidence":"High","gaps":["Relative contribution of cis versus trans presentation in physiological immune responses not quantified","Whether cis signaling activates distinct downstream programs versus trans signaling unknown"]},{"year":2010,"claim":"Showing that DNA methylation regulates IL15RA expression — specifically that a CpG island controls alternative exon-skipping variants — identified an epigenetic mechanism for modulating receptor availability on immune cells.","evidence":"5-azacitidine treatment of PBMCs with quantitative RT-PCR for transcript variants","pmids":["21097393"],"confidence":"Medium","gaps":["Whether methylation-dependent regulation operates in non-immune tissues not tested","Functional consequences of individual splice variants not determined","No bisulfite sequencing of the CpG island provided"]},{"year":2014,"claim":"Discovery of a non-canonical IL15RA signaling pathway (JAK1–STAT1/2–AKT–ERK, independent of IL-2Rβ/γc and STAT5) in triple-negative breast cancer cells revealed that IL15RA can drive autocrine pro-tumorigenic signaling in the absence of the conventional co-receptor chains.","evidence":"RNAi knockdown of IL15RA with phosphoprotein/western blot signaling analysis and co-culture paracrine assays in breast cancer cell lines","pmids":["24980552"],"confidence":"Medium","gaps":["The molecular mechanism by which IL15RA engages JAK1 without IL-2Rβ/γc is unknown","Whether a distinct co-receptor substitutes for β/γc not investigated","Not independently replicated in other cancer types at that time"]},{"year":2014,"claim":"Muscle-specific deletion of IL15RA established a cell-autonomous role for the receptor in restraining mitochondrial biogenesis and oxidative metabolism in skeletal muscle, distinct from its immune function.","evidence":"MCK-Cre conditional knockout mice; isometric contractile and fatigue assays; mitochondrial genome (COXII) quantification","pmids":["25505029"],"confidence":"High","gaps":["Whether IL15RA acts through IL-15 binding or a ligand-independent mechanism in muscle not resolved","Downstream signaling pathway linking IL15RA to mitochondrial biogenesis in muscle not identified"]},{"year":2017,"claim":"Two independent findings expanded IL15RA's tissue-autonomous functions: (1) IL15RA is required for osteoblast mineralization and RANKL/OPG-mediated osteoclast coupling in bone, and (2) IL-15Rα+ myeloid cells produce IGF-1 in response to IL-15, promoting tumor growth — linking the receptor to both skeletal homeostasis and the tumor microenvironment.","evidence":"Il15ra−/− mice with osteogenic cultures, ENPP1 activity assays, shRNA knockdown (bone); in vivo IL-15 injection with IGF-1 blocking in xenograft models (myeloid/tumor)","pmids":["28602725","29255466"],"confidence":"High","gaps":["Mechanism by which IL15RA regulates ENPP1 activity in osteoblasts unknown","Whether the IGF-1 axis operates in immunocompetent hosts not fully established","Signaling pathway downstream of IL15RA in osteoblasts not identified"]},{"year":2018,"claim":"Ultrastructural analysis of IL15RA-null muscle resolved that the increased mitochondrial capacity involves higher cristae density mediated by elevated OPA1 and cardiolipin, without fiber-type switching, establishing a role for IL15RA in regulating mitochondrial inner membrane architecture.","evidence":"Il15ra whole-body knockout; electron microscopy of subsarcolemmal and A-band mitochondria; OPA1 and cardiolipin quantification","pmids":["30301784"],"confidence":"High","gaps":["Whether IL15RA directly or indirectly regulates OPA1 expression/processing is unknown","Mechanism linking IL15RA loss to cardiolipin accumulation not defined"]},{"year":2020,"claim":"Demonstrating that IL-15 stimulation of IL15RA-expressing chondrocytes induces MMP-1 and MMP-3 release extended the receptor's non-immune functions to cartilage matrix remodeling.","evidence":"Ex vivo cartilage explant culture with IL-15; MMP release assays and immunohistochemistry","pmids":["32793194"],"confidence":"Medium","gaps":["Downstream signaling pathway from IL15RA to MMP induction in chondrocytes not identified","Whether this contributes to osteoarthritis pathology in vivo not tested"]},{"year":2024,"claim":"Identification of the IL15RA–STAT3–GPX4/ACSL3 axis in pancreatic cancer revealed that IL-15 from stellate cells confers ferroptosis resistance to tumor cells, adding STAT3 as another non-canonical downstream effector of IL15RA in cancer.","evidence":"Pancreatic stellate cell–cancer cell co-culture; in vitro and in vivo ferroptosis assays; STAT3 pathway and GPX4/ACSL3 expression analysis","pmids":["39396119"],"confidence":"Medium","gaps":["Whether IL15RA engages STAT3 directly or through intermediate kinases not resolved","Generalizability to other cancer types not tested"]},{"year":2025,"claim":"Upstream regulation of IL15RA was further defined: STAT1 transcriptionally activates the IL15RA promoter and METTL3-mediated m6A methylation stabilizes its mRNA; IL15RA then drives renal cell carcinoma metastasis via NF-κB/ZEB1, revealing a feedforward regulatory circuit.","evidence":"STAT1 promoter binding assay; m6A methylation analysis; NF-κB/ZEB1 metastasis assays in ccRCC cells","pmids":["41168330"],"confidence":"Medium","gaps":["Direct ChIP-seq validation of STAT1 binding not fully detailed","Whether METTL3-mediated stabilization is specific to IL15RA or part of a broader program unknown","NF-κB/ZEB1 activation mechanism downstream of IL15RA not defined"]},{"year":null,"claim":"The mechanism by which IL15RA regulates mitochondrial ultrastructure (OPA1/cardiolipin) in muscle, the identity of a potential co-receptor enabling non-canonical signaling in cancer cells lacking IL-2Rβ/γc, and the structural basis for pathway-selective signaling (STAT5 versus STAT1/2 versus STAT3) across different cell contexts remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of how IL15RA selects among JAK/STAT pathways in different cell types","Ligand-independent functions of IL15RA in non-immune tissues not formally tested","Whether muscle and bone phenotypes share a common downstream signaling mechanism is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,8,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,8,9]}],"complexes":[],"partners":["IL15","JAK1","STAT5","STAT1","STAT3","GPX4"],"other_free_text":[]},"mechanistic_narrative":"IL15RA encodes the private alpha subunit of the interleukin-15 receptor, functioning primarily as a high-affinity ligand-binding chain that captures IL-15 and presents it in trans to neighboring cells or in cis on the same cell to activate downstream signaling through the shared IL-2Rβ/γc heterodimer. IL15RA binds IL-15 with ~1000-fold higher affinity than IL-2Rα binds IL-2, and its cytoplasmic domain is dispensable for mitogenic signaling; cis presentation on CD8+ T cells enhances STAT5 phosphorylation, proliferation, and cytotoxic potential [PMID:8530383, PMID:19180469]. In cancer cells lacking IL-2Rβ/γc, IL15RA activates a non-canonical JAK1–STAT1/STAT2–AKT–ERK pathway promoting proliferation and survival, and in pancreatic cancer it engages a STAT3–GPX4/ACSL3 axis that confers ferroptosis resistance [PMID:24980552, PMID:39396119]. Beyond immune signaling, IL15RA has cell-autonomous roles in skeletal muscle, where its loss increases mitochondrial content, cristae density, and oxidative capacity, and in bone, where it is required for normal osteoblast-driven mineralization and osteoblast–osteoclast coupling [PMID:25505029, PMID:30301784, PMID:28602725]."},"prefetch_data":{"uniprot":{"accession":"Q13261","full_name":"Interleukin-15 receptor subunit alpha","aliases":[],"length_aa":267,"mass_kda":28.2,"function":"High-affinity receptor for interleukin-15 (PubMed:8530383). Can signal both in cis and trans where IL15R from one subset of cells presents IL15 to neighboring IL2RG-expressing cells (By similarity). In neutrophils, binds and activates kinase SYK in response to IL15 stimulation (PubMed:15123770). In neutrophils, required for IL15-induced phagocytosis in a SYK-dependent manner (PubMed:15123770). Expression of different isoforms may alter or interfere with signal transduction (PubMed:10480910) Does not bind IL15 Does not bind IL15 Does not bind IL15 Does not bind IL15","subcellular_location":"Secreted, extracellular space","url":"https://www.uniprot.org/uniprotkb/Q13261/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL15RA","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL15RA","total_profiled":1310},"omim":[{"mim_id":"601070","title":"INTERLEUKIN 15 RECEPTOR, ALPHA; IL15RA","url":"https://www.omim.org/entry/601070"},{"mim_id":"600554","title":"INTERLEUKIN 15; IL15","url":"https://www.omim.org/entry/600554"},{"mim_id":"308380","title":"INTERLEUKIN 2 RECEPTOR, GAMMA; IL2RG","url":"https://www.omim.org/entry/308380"},{"mim_id":"147680","title":"INTERLEUKIN 2; IL2","url":"https://www.omim.org/entry/147680"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IL15RA"},"hgnc":{"alias_symbol":["CD215","IL-15RA"],"prev_symbol":[]},"alphafold":{"accession":"Q13261","domains":[{"cath_id":"2.20.28.230","chopping":"31-104","consensus_level":"medium","plddt":95.3216,"start":31,"end":104}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13261","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13261-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13261-F1-predicted_aligned_error_v6.png","plddt_mean":64.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL15RA","jax_strain_url":"https://www.jax.org/strain/search?query=IL15RA"},"sequence":{"accession":"Q13261","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13261.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13261/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13261"}},"corpus_meta":[{"pmid":"8530383","id":"PMC_8530383","title":"Functional characterization of the human interleukin-15 receptor alpha chain and close linkage of IL15RA and IL2RA genes.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8530383","citation_count":309,"is_preprint":false},{"pmid":"19180469","id":"PMC_19180469","title":"Expression of IL-15RA or an IL-15/IL-15RA fusion on CD8+ T cells modifies adoptively transferred T-cell function in cis.","date":"2009","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19180469","citation_count":47,"is_preprint":false},{"pmid":"24980552","id":"PMC_24980552","title":"IL15RA drives antagonistic mechanisms of cancer development and immune control in lymphocyte-enriched triple-negative breast cancers.","date":"2014","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/24980552","citation_count":44,"is_preprint":false},{"pmid":"28602725","id":"PMC_28602725","title":"IL15RA is required for osteoblast function and bone mineralization.","date":"2017","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/28602725","citation_count":31,"is_preprint":false},{"pmid":"32793194","id":"PMC_32793194","title":"IL-15 and IL15RA in Osteoarthritis: Association With Symptoms and Protease Production, but Not Structural Severity.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32793194","citation_count":30,"is_preprint":false},{"pmid":"21689944","id":"PMC_21689944","title":"Association between interleukin 15 receptor, alpha (IL15RA) polymorphism and Korean patients with ossification of the posterior longitudinal ligament.","date":"2011","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/21689944","citation_count":19,"is_preprint":false},{"pmid":"25505029","id":"PMC_25505029","title":"Muscle-specific deletion of exons 2 and 3 of the IL15RA gene in mice: effects on contractile properties of fast and slow muscles.","date":"2014","source":"Journal of applied physiology (Bethesda, Md. : 1985)","url":"https://pubmed.ncbi.nlm.nih.gov/25505029","citation_count":17,"is_preprint":false},{"pmid":"25387549","id":"PMC_25387549","title":"Association between single nucleotide polymorphism of IL15RA gene with susceptibility to ossification of the posterior longitudinal ligament of the spine.","date":"2014","source":"Journal of orthopaedic surgery and research","url":"https://pubmed.ncbi.nlm.nih.gov/25387549","citation_count":16,"is_preprint":false},{"pmid":"29255466","id":"PMC_29255466","title":"CD215+ Myeloid Cells Respond to Interleukin 15 Stimulation and Promote Tumor Progression.","date":"2017","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29255466","citation_count":9,"is_preprint":false},{"pmid":"30301784","id":"PMC_30301784","title":"Mitochondrial ultrastructural adaptations in fast muscles of mice lacking IL15RA.","date":"2018","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/30301784","citation_count":9,"is_preprint":false},{"pmid":"39396119","id":"PMC_39396119","title":"IL15RA-STAT3-GPX4/ACSL3 signaling leads to ferroptosis resistance in pancreatic cancer.","date":"2024","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/39396119","citation_count":9,"is_preprint":false},{"pmid":"36009415","id":"PMC_36009415","title":"IL-15/IL-15Rα in SJS/TEN: Relevant Expression of IL15 and IL15RA in Affected Skin.","date":"2022","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/36009415","citation_count":9,"is_preprint":false},{"pmid":"21097393","id":"PMC_21097393","title":"Tissue-specific expression of IL-15RA alternative splicing transcripts and its regulation by DNA methylation.","date":"2010","source":"European cytokine 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The cytoplasmic domain of IL-15Rα is dispensable for mitogenic signaling, indicating the primary role of the alpha chain is to confer high-affinity ligand binding. At high IL-15 concentrations, signaling can occur through the IL-2Rβ/γ heterodimer in the absence of the alpha subunit.\",\n      \"method\": \"Binding assays with differentially spliced receptor variants; cytoplasmic domain deletion mutants; mitogenic signaling assays in cell lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (binding assays, deletion mutagenesis, functional signaling assays) in a highly cited foundational paper\",\n      \"pmids\": [\"8530383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-15Rα expressed on CD8+ T cells can present IL-15 in cis (to the same cell), enhancing IL-15-mediated STAT5 phosphorylation, proliferation in vivo, and viability. A chimeric IL-15/IL-15Rα fusion construct autonomously enhances viability, proliferation, and cytotoxic potential of primary CD8+ T cells.\",\n      \"method\": \"RNA nucleofection of naive CD8+ T cells with IL-15Rα or IL-15/IL-15Rα fusion constructs; STAT5 phosphorylation assay; in vivo adoptive transfer proliferation assay\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (signaling assay, in vivo proliferation, viability, cytotoxicity) in a single study\",\n      \"pmids\": [\"19180469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In triple-negative breast cancer cells expressing IL15RA but lacking IL2RB and IL2RG, IL15RA signals through a non-canonical pathway activating JAK1, STAT1, STAT2, AKT, PRAS40, and ERK1/2 (but not STAT5 or JAK2), promoting cell proliferation, migration, and blocking apoptosis in an autocrine manner. IL15RA-expressing cancer cells also activate PBMCs in a paracrine manner.\",\n      \"method\": \"RNAi-mediated knockdown of IL15RA; phosphoprotein/western blot analysis of downstream signaling; co-culture paracrine assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNAi loss-of-function combined with phosphoproteomic readouts, but single lab\",\n      \"pmids\": [\"24980552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Muscle-specific deletion of IL15RA exons 2 and 3 in mice causes a pro-oxidative shift in skeletal muscle contractile phenotype, increased fatigue resistance in fast-twitch (EDL) muscles, and a twofold increase in mitochondrial genome content (COXII), alongside reduced circulating IL-15 protein levels.\",\n      \"method\": \"Cre-loxP conditional knockout (MCK-Cre); isometric contractile and fatigue assays; COXII gene copy quantification\",\n      \"journal\": \"Journal of applied physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean muscle-specific KO with defined functional phenotypic readouts (contractile, fatigue, mitochondrial content)\",\n      \"pmids\": [\"25505029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL15RA plays a cell-autonomous role in osteoblast function and bone mineralization: Il15ra-/- mice show decreased bone mineralization in vivo and in primary osteogenic cultures. Il15ra-/- osteogenic cultures exhibit a reduced RANKL/OPG mRNA ratio, indicating defective osteoblast/osteoclast coupling. shRNA silencing of Il15ra in MC3T3-E1 cells decreased ENPP1 enzymatic activity.\",\n      \"method\": \"Whole-body Il15ra knockout mouse; primary osteogenic culture mineralization assay; qPCR; shRNA knockdown; ENPP1 activity assay; transcriptome analysis\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with in vivo and in vitro orthogonal assays plus enzymatic activity readout\",\n      \"pmids\": [\"28602725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of IL15RA in mice results in higher mitochondrial content and increased cristae density in subsarcolemmal and A-band mitochondrial subpopulations of fast-twitch (EDL) skeletal muscle, associated with elevated OPA1 protein and cardiolipin levels, without changes in myosin heavy chain fiber-type distribution.\",\n      \"method\": \"Il15ra whole-body knockout; electron microscopy; immunostaining for MyHC isoforms; OPA1 and cardiolipin quantification\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO model with ultrastructural (EM) and biochemical orthogonal readouts\",\n      \"pmids\": [\"30301784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-15RA gene expression is regulated by DNA methylation: treatment of PBMCs with the DNA methyltransferase inhibitor 5-azacitidine significantly increased IL-15RA copy number, specifically affecting alternative exon-skipping variants of the Var1 transcript (Del2, Del3, Del2,3), consistent with a CpG island in the Var1 but not Var2 regulatory region.\",\n      \"method\": \"5-azacitidine treatment; quantitative RT-PCR; transcript variant analysis\",\n      \"journal\": \"European cytokine network\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological inhibition with transcript-level readouts, single method but consistent with CpG island location\",\n      \"pmids\": [\"21097393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD215+ (IL-15Rα+) myeloid cells respond to IL-15 stimulation by producing IGF-1, which promotes tumor growth; blocking IGF-1 reduced the tumor-promoting effect of IL-15 in xenograft models.\",\n      \"method\": \"In vivo IL-15 injection in NSI and C57BL/6 tumor-bearing mice; flow cytometry; IGF-1 blocking antibody; xenograft tumor models\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo functional rescue/blocking experiment with defined mechanistic readout, single lab\",\n      \"pmids\": [\"29255466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In pancreatic cancer, IL-15 secreted by pancreatic stellate cells activates the IL15RA-STAT3-GPX4/ACSL3 axis in cancer cells, simultaneously upregulating both GPX4 and ACSL3 to prevent lipid peroxidation, conferring ferroptosis resistance both in vitro and in vivo.\",\n      \"method\": \"PSC-cancer cell co-culture system; in vitro and in vivo ferroptosis assays; STAT3 pathway analysis; GPX4/ACSL3 expression assays\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo experiments with defined pathway, single lab\",\n      \"pmids\": [\"39396119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STAT1 binds to the IL15RA promoter to enhance IL15RA mRNA expression, and METTL3-mediated RNA m6A methylation stabilizes IL15RA transcripts; IL15RA in turn promotes ccRCC metastasis via activation of the NF-κB/ZEB1 axis.\",\n      \"method\": \"Promoter binding assay (STAT1-ChIP implied); m6A methylation analysis; metastasis assays; NF-κB/ZEB1 pathway analysis in ccRCC cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — mechanistic pathway dissection with upstream regulators identified, but single lab with limited methodological detail in abstract\",\n      \"pmids\": [\"41168330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-15 stimulation of cartilage explants significantly increased release of MMP-1 and MMP-3, demonstrating that IL-15Rα-expressing chondrocytes respond to IL-15 by upregulating matrix-degrading proteases.\",\n      \"method\": \"Ex vivo cartilage explant culture with IL-15; MMP-1 and MMP-3 release assay; immunohistochemistry for IL-15Rα in chondrocytes\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ex vivo functional assay with defined protease output, but limited mechanistic depth\",\n      \"pmids\": [\"32793194\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL15RA encodes the high-affinity private alpha subunit of the IL-15 receptor that binds IL-15 with extremely high affinity (its cytoplasmic domain is dispensable for signaling); it can present IL-15 in trans to neighboring cells or in cis to the same cell (e.g., on CD8+ T cells), activating downstream JAK/STAT5, JAK1/STAT1/STAT2, AKT, and ERK signaling depending on cellular context; in cancer cells lacking IL-2Rβ/γ it drives a non-canonical JAK1-STAT1/2-AKT-ERK pathway, and in pancreatic cancer activates a STAT3-GPX4/ACSL3 ferroptosis-resistance axis; in skeletal muscle and bone, IL15RA plays cell-autonomous roles in regulating mitochondrial ultrastructure, oxidative metabolism, and osteoblast-driven bone mineralization and osteoclast coupling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL15RA encodes the private alpha subunit of the interleukin-15 receptor, functioning primarily as a high-affinity ligand-binding chain that captures IL-15 and presents it in trans to neighboring cells or in cis on the same cell to activate downstream signaling through the shared IL-2Rβ/γc heterodimer. IL15RA binds IL-15 with ~1000-fold higher affinity than IL-2Rα binds IL-2, and its cytoplasmic domain is dispensable for mitogenic signaling; cis presentation on CD8+ T cells enhances STAT5 phosphorylation, proliferation, and cytotoxic potential [PMID:8530383, PMID:19180469]. In cancer cells lacking IL-2Rβ/γc, IL15RA activates a non-canonical JAK1–STAT1/STAT2–AKT–ERK pathway promoting proliferation and survival, and in pancreatic cancer it engages a STAT3–GPX4/ACSL3 axis that confers ferroptosis resistance [PMID:24980552, PMID:39396119]. Beyond immune signaling, IL15RA has cell-autonomous roles in skeletal muscle, where its loss increases mitochondrial content, cristae density, and oxidative capacity, and in bone, where it is required for normal osteoblast-driven mineralization and osteoblast–osteoclast coupling [PMID:25505029, PMID:30301784, PMID:28602725].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing that IL15RA is the high-affinity ligand-binding subunit of the IL-15 receptor — with an affinity far exceeding IL-2Rα for IL-2 — and that its cytoplasmic domain is dispensable for signaling resolved the fundamental question of how IL-15 specificity is encoded within the shared IL-2/IL-15 receptor system.\",\n      \"evidence\": \"Binding assays with spliced receptor variants, cytoplasmic domain deletion mutants, and mitogenic signaling assays in cell lines\",\n      \"pmids\": [\"8530383\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the ~1000-fold affinity difference unresolved\", \"Whether IL15RA has signaling-independent functions not addressed\", \"Physiological cell types requiring alpha chain versus beta/gamma-only signaling not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating that IL15RA on CD8+ T cells can present IL-15 in cis — not only in trans from accessory cells — expanded the receptor's functional repertoire beyond a simple antigen-presenting-cell-to-T-cell relay and showed autonomous enhancement of T cell proliferation and cytotoxicity.\",\n      \"evidence\": \"RNA nucleofection of IL-15Rα or IL-15/IL-15Rα fusion constructs into naive CD8+ T cells; STAT5 phosphorylation and in vivo adoptive transfer proliferation assays\",\n      \"pmids\": [\"19180469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of cis versus trans presentation in physiological immune responses not quantified\", \"Whether cis signaling activates distinct downstream programs versus trans signaling unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showing that DNA methylation regulates IL15RA expression — specifically that a CpG island controls alternative exon-skipping variants — identified an epigenetic mechanism for modulating receptor availability on immune cells.\",\n      \"evidence\": \"5-azacitidine treatment of PBMCs with quantitative RT-PCR for transcript variants\",\n      \"pmids\": [\"21097393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether methylation-dependent regulation operates in non-immune tissues not tested\", \"Functional consequences of individual splice variants not determined\", \"No bisulfite sequencing of the CpG island provided\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery of a non-canonical IL15RA signaling pathway (JAK1–STAT1/2–AKT–ERK, independent of IL-2Rβ/γc and STAT5) in triple-negative breast cancer cells revealed that IL15RA can drive autocrine pro-tumorigenic signaling in the absence of the conventional co-receptor chains.\",\n      \"evidence\": \"RNAi knockdown of IL15RA with phosphoprotein/western blot signaling analysis and co-culture paracrine assays in breast cancer cell lines\",\n      \"pmids\": [\"24980552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The molecular mechanism by which IL15RA engages JAK1 without IL-2Rβ/γc is unknown\", \"Whether a distinct co-receptor substitutes for β/γc not investigated\", \"Not independently replicated in other cancer types at that time\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Muscle-specific deletion of IL15RA established a cell-autonomous role for the receptor in restraining mitochondrial biogenesis and oxidative metabolism in skeletal muscle, distinct from its immune function.\",\n      \"evidence\": \"MCK-Cre conditional knockout mice; isometric contractile and fatigue assays; mitochondrial genome (COXII) quantification\",\n      \"pmids\": [\"25505029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IL15RA acts through IL-15 binding or a ligand-independent mechanism in muscle not resolved\", \"Downstream signaling pathway linking IL15RA to mitochondrial biogenesis in muscle not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two independent findings expanded IL15RA's tissue-autonomous functions: (1) IL15RA is required for osteoblast mineralization and RANKL/OPG-mediated osteoclast coupling in bone, and (2) IL-15Rα+ myeloid cells produce IGF-1 in response to IL-15, promoting tumor growth — linking the receptor to both skeletal homeostasis and the tumor microenvironment.\",\n      \"evidence\": \"Il15ra−/− mice with osteogenic cultures, ENPP1 activity assays, shRNA knockdown (bone); in vivo IL-15 injection with IGF-1 blocking in xenograft models (myeloid/tumor)\",\n      \"pmids\": [\"28602725\", \"29255466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which IL15RA regulates ENPP1 activity in osteoblasts unknown\", \"Whether the IGF-1 axis operates in immunocompetent hosts not fully established\", \"Signaling pathway downstream of IL15RA in osteoblasts not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Ultrastructural analysis of IL15RA-null muscle resolved that the increased mitochondrial capacity involves higher cristae density mediated by elevated OPA1 and cardiolipin, without fiber-type switching, establishing a role for IL15RA in regulating mitochondrial inner membrane architecture.\",\n      \"evidence\": \"Il15ra whole-body knockout; electron microscopy of subsarcolemmal and A-band mitochondria; OPA1 and cardiolipin quantification\",\n      \"pmids\": [\"30301784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IL15RA directly or indirectly regulates OPA1 expression/processing is unknown\", \"Mechanism linking IL15RA loss to cardiolipin accumulation not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating that IL-15 stimulation of IL15RA-expressing chondrocytes induces MMP-1 and MMP-3 release extended the receptor's non-immune functions to cartilage matrix remodeling.\",\n      \"evidence\": \"Ex vivo cartilage explant culture with IL-15; MMP release assays and immunohistochemistry\",\n      \"pmids\": [\"32793194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling pathway from IL15RA to MMP induction in chondrocytes not identified\", \"Whether this contributes to osteoarthritis pathology in vivo not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of the IL15RA–STAT3–GPX4/ACSL3 axis in pancreatic cancer revealed that IL-15 from stellate cells confers ferroptosis resistance to tumor cells, adding STAT3 as another non-canonical downstream effector of IL15RA in cancer.\",\n      \"evidence\": \"Pancreatic stellate cell–cancer cell co-culture; in vitro and in vivo ferroptosis assays; STAT3 pathway and GPX4/ACSL3 expression analysis\",\n      \"pmids\": [\"39396119\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IL15RA engages STAT3 directly or through intermediate kinases not resolved\", \"Generalizability to other cancer types not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Upstream regulation of IL15RA was further defined: STAT1 transcriptionally activates the IL15RA promoter and METTL3-mediated m6A methylation stabilizes its mRNA; IL15RA then drives renal cell carcinoma metastasis via NF-κB/ZEB1, revealing a feedforward regulatory circuit.\",\n      \"evidence\": \"STAT1 promoter binding assay; m6A methylation analysis; NF-κB/ZEB1 metastasis assays in ccRCC cells\",\n      \"pmids\": [\"41168330\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ChIP-seq validation of STAT1 binding not fully detailed\", \"Whether METTL3-mediated stabilization is specific to IL15RA or part of a broader program unknown\", \"NF-κB/ZEB1 activation mechanism downstream of IL15RA not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanism by which IL15RA regulates mitochondrial ultrastructure (OPA1/cardiolipin) in muscle, the identity of a potential co-receptor enabling non-canonical signaling in cancer cells lacking IL-2Rβ/γc, and the structural basis for pathway-selective signaling (STAT5 versus STAT1/2 versus STAT3) across different cell contexts remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of how IL15RA selects among JAK/STAT pathways in different cell types\", \"Ligand-independent functions of IL15RA in non-immune tissues not formally tested\", \"Whether muscle and bone phenotypes share a common downstream signaling mechanism is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 8, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 8, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IL15\", \"JAK1\", \"STAT5\", \"STAT1\", \"STAT3\", \"GPX4\"],\n    \"other_free_text\": []\n  }\n}\n```"}