{"gene":"LRRC25","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2017,"finding":"LRRC25 specifically binds to ISG15-associated RIG-I upon RNA virus infection and promotes the interaction between RIG-I and the autophagic cargo receptor p62, mediating selective autophagic degradation of RIG-I to negatively regulate type I IFN signaling. Depletion of either LRRC25 or ISG15 abrogates the RIG-I–p62 interaction and autophagic degradation of RIG-I.","method":"Co-immunoprecipitation, knockdown/knockout loss-of-function, autophagic flux assays, RNA virus infection models","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic depletion of both LRRC25 and ISG15 with orthogonal phenotypic readouts, multiple mechanistic validations in one focused study","pmids":["29288164"],"is_preprint":false},{"year":2017,"finding":"LRRC25 acts as a negative regulator of NF-κB signaling: its LRR domain directly interacts with the Rel Homology domain (RHD) of p65/RelA, enhances the interaction between p65/RelA and the autophagic cargo receptor p62, and thereby promotes autophagic degradation of p65/RelA. Knockout of LRRC25 potentiates NF-κB activation and inflammatory cytokine production.","method":"Ectopic overexpression, CRISPR/Cas9 knockout, domain-mapping Co-IP (LRR domain vs. RHD), autophagic degradation assays, cytokine measurement","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain-mapping Co-IP, CRISPR knockout with defined phenotype, multiple orthogonal methods in one focused study","pmids":["29044191"],"is_preprint":false},{"year":2017,"finding":"LRRC25 is a type I transmembrane molecule highly expressed in primary myeloid cells (granulocytes, monocytes) and is required for ATRA-induced terminal granulocytic differentiation; knockdown by siRNA/shRNA or knockout by CRISPR-Cas9 attenuates ATRA-induced differentiation, and restoration of LRRC25 in knockout cells rescues differentiation.","method":"siRNA/shRNA knockdown, CRISPR-Cas9 knockout, rescue experiments, flow cytometry for differentiation markers, subcellular localization analysis","journal":"Protein & cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple loss-of-function approaches (siRNA, shRNA, CRISPR KO) with rescue, defined granulocytic differentiation phenotype, single lab but orthogonal methods","pmids":["28536942"],"is_preprint":false},{"year":2018,"finding":"Loss of LRRC25 in vivo accelerates pathological cardiac hypertrophy by promoting TGF-β1/Smad2/3 signaling and NF-κB activation; LRRC25 knockout mice show exacerbated cardiac fibrosis, dysfunction, and inflammation in response to aortic banding or angiotensin II stimulation, and inhibition of TGF-β1 or NF-κB abolishes the pro-hypertrophic effects of LRRC25 deficiency in vitro.","method":"LRRC25 knockout mouse model, aortic banding surgery, angiotensin II stimulation, western blot for phospho-Smad2/3, NF-κB activation assays, pharmacological inhibition","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo KO with defined cardiac phenotype and pathway inhibitor rescue, single lab, limited mechanistic resolution of direct binding","pmids":["30340835"],"is_preprint":false},{"year":2020,"finding":"FMDV nonstructural protein 3A interacts with G3BP1 to upregulate LRRC25 expression, which then promotes autophagic degradation of G3BP1, thereby inhibiting G3BP1-mediated RIG-I/MDA5 (RLH) signaling and suppressing type I IFN responses. Similar effects were observed with 3A proteins from other picornaviruses (SVV, EV71, EMCV).","method":"Co-immunoprecipitation, overexpression of viral 3A proteins, siRNA knockdown, western blot, IFN reporter assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for 3A–G3BP1 interaction, LRRC25 overexpression/knockdown with defined IFN phenotype, replicated across multiple picornavirus 3A proteins, single lab","pmids":["31996428"],"is_preprint":false},{"year":2023,"finding":"LRRC25 negatively regulates anti-tuberculosis immunity in microglia: silencing LRRC25 in BV2 cells infected with H37Rv (Mycobacterium tuberculosis) decreases the proportion of infected cells and significantly increases IFN-γ and ISG15 secretion, indicating that LRRC25 suppresses IFN-γ secretion and degrades free ISG15 in this context.","method":"siRNA knockdown of LRRC25 in BV2 microglia, H37Rv infection, ELISA for IFN-γ and ISG15, flow cytometry, qPCR, immunofluorescence","journal":"Microorganisms","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — siRNA loss-of-function with defined immunological phenotypes, single lab, single method per endpoint","pmids":["37894158"],"is_preprint":false},{"year":2025,"finding":"LRRC25 is specifically expressed in myeloid cells including tumor-associated macrophages (TAMs); Lrrc25 deficiency in the tumor microenvironment reprograms TAMs toward an anti-tumor phenotype, elevates the Nox2-ROS-Nlrp3-IL1β pathway in TAMs, and enhances CD8+ T cell infiltration and activation to suppress tumor growth in multiple murine models.","method":"Lrrc25-deficient mouse models, multiple murine tumor models, TAM phenotyping, Nlrp3-IL1β pathway analysis, CD8+ T cell flow cytometry","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic KO with multiple tumor models, pathway identification (Nox2-ROS-Nlrp3-IL1β), defined immune cell phenotypes, single lab","pmids":["40279244"],"is_preprint":false},{"year":2024,"finding":"LRRC25 protein is expressed in both cell membranes and cytoplasm in a punctate pattern in astrocytes, microglia, and neurons, and its expression is age- and brain-region-dependent in mice; LRRC25 protein levels are elevated in the cortex and hippocampus of two mouse models of Alzheimer's disease (APdeltaE9 and 3xTg) and in AD patient brains.","method":"Immunoblot, immunofluorescence, subcellular localization analysis in cell lines and mouse brain, comparison across AD mouse models and human tissue","journal":"Frontiers in molecular neuroscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization established by immunofluorescence/fractionation but without direct functional consequence demonstrated; expression changes in AD models are associative","pmids":["38476461"],"is_preprint":false}],"current_model":"LRRC25 is a type I transmembrane leucine-rich repeat protein expressed predominantly in myeloid cells that functions as a broad negative regulator of innate immune signaling: it acts as a secondary autophagic receptor by binding ISG15-modified RIG-I and bridging it to p62 for selective autophagic degradation (suppressing type I IFN responses), similarly promotes autophagic degradation of p65/RelA via its LRR–RHD interaction (suppressing NF-κB), is required for ATRA-induced granulocytic differentiation, regulates anti-tuberculosis IFN-γ secretion in microglia, and controls tumor-associated macrophage inflammatory programming through the Nox2-ROS-Nlrp3-IL1β axis."},"narrative":{"mechanistic_narrative":"LRRC25 is a type I transmembrane leucine-rich repeat protein expressed predominantly in myeloid cells that acts as a broad negative regulator of innate immune signaling by coupling immune effectors to selective autophagic degradation [PMID:29288164, PMID:28536942]. In antiviral signaling, LRRC25 binds ISG15-conjugated RIG-I and bridges it to the autophagic cargo receptor p62, driving selective autophagic turnover of RIG-I and dampening type I IFN responses; loss of either LRRC25 or ISG15 abolishes the RIG-I–p62 interaction [PMID:29288164]. The same degradative logic applies to NF-κB signaling, where the LRR domain of LRRC25 directly engages the Rel Homology domain of p65/RelA and enhances its p62-dependent autophagic degradation, so that LRRC25 loss potentiates NF-κB activation and inflammatory cytokine output [PMID:29044191]. Picornaviruses exploit this axis: viral 3A proteins acting through G3BP1 upregulate LRRC25, which then degrades G3BP1 to suppress RIG-I/MDA5 signaling and IFN induction [PMID:31996428]. Beyond pathogen sensing, LRRC25 is required for ATRA-induced terminal granulocytic differentiation [PMID:28536942], restrains anti-tuberculosis IFN-γ secretion and free ISG15 in microglia [PMID:37894158], and shapes tumor-associated macrophage programming, with its deficiency activating a Nox2-ROS-Nlrp3-IL1β axis that promotes anti-tumor immunity [PMID:40279244]. In vivo, LRRC25 loss aggravates pathological cardiac hypertrophy through enhanced TGF-β1/Smad2/3 and NF-κB signaling [PMID:30340835].","teleology":[{"year":2017,"claim":"Established LRRC25 as a selective autophagy adaptor that terminates antiviral signaling by linking ISG15-modified RIG-I to p62 for degradation, answering how RIG-I is cleared to limit type I IFN.","evidence":"Reciprocal Co-IP, knockdown/knockout of LRRC25 and ISG15, autophagic flux assays in RNA virus infection models","pmids":["29288164"],"confidence":"High","gaps":["Structural basis of ISG15-RIG-I recognition by LRRC25 not resolved","Whether membrane anchoring is required for the bridging function untested"]},{"year":2017,"claim":"Showed the same LRRC25-p62 degradative mechanism operates on NF-κB, with the LRR domain directly binding the p65/RelA RHD, defining a shared logic across two innate pathways.","evidence":"Domain-mapping Co-IP (LRR vs RHD), CRISPR/Cas9 knockout, autophagic degradation and cytokine assays","pmids":["29044191"],"confidence":"High","gaps":["Direct LRR-RHD binding not validated by purified-protein reconstitution","Selectivity for p65 over other Rel-family members not addressed"]},{"year":2017,"claim":"Identified a developmental role distinct from immune suppression, showing LRRC25 is required for ATRA-induced granulocytic differentiation in myeloid cells.","evidence":"siRNA/shRNA knockdown, CRISPR-KO with rescue, flow cytometry for differentiation markers","pmids":["28536942"],"confidence":"High","gaps":["Molecular link between LRRC25 and the ATRA differentiation program unknown","Whether the autophagy adaptor function underlies differentiation untested"]},{"year":2018,"claim":"Extended LRRC25 function to cardiac pathology, showing its loss accelerates hypertrophy via TGF-β1/Smad2/3 and NF-κB, consistent with its role as a brake on inflammatory signaling.","evidence":"LRRC25 knockout mouse, aortic banding and angiotensin II models, phospho-Smad2/3 blots, pathway inhibitor rescue","pmids":["30340835"],"confidence":"Medium","gaps":["Direct binding partners in the TGF-β1/Smad pathway not mapped","Cell type driving the cardiac phenotype not defined"]},{"year":2020,"claim":"Revealed that picornaviruses co-opt LRRC25, with viral 3A proteins inducing it to degrade G3BP1 and suppress RLH signaling, expanding its substrate repertoire and showing pathogen exploitation.","evidence":"Co-IP, viral 3A overexpression, siRNA knockdown, IFN reporter assays across multiple picornaviruses","pmids":["31996428"],"confidence":"Medium","gaps":["Whether G3BP1 degradation uses the same p62-autophagy route as RIG-I not directly shown","Mechanism of 3A-driven LRRC25 upregulation unresolved"]},{"year":2023,"claim":"Demonstrated LRRC25 restrains anti-tuberculosis immunity in microglia by suppressing IFN-γ secretion and degrading free ISG15, extending its immunosuppressive role to CNS-resident myeloid cells.","evidence":"siRNA knockdown in BV2 microglia, H37Rv infection, ELISA for IFN-γ and ISG15","pmids":["37894158"],"confidence":"Medium","gaps":["Single loss-of-function method per endpoint without rescue","Direct mechanism connecting LRRC25 to IFN-γ control not defined"]},{"year":2025,"claim":"Showed LRRC25 deficiency reprograms tumor-associated macrophages toward anti-tumor activity via a Nox2-ROS-Nlrp3-IL1β axis, linking its myeloid expression to tumor immune control.","evidence":"Lrrc25-deficient mice, multiple murine tumor models, TAM phenotyping, CD8+ T cell flow cytometry","pmids":["40279244"],"confidence":"Medium","gaps":["Direct molecular target of LRRC25 within the Nox2-Nlrp3 axis not identified","Whether autophagy adaptor activity drives TAM reprogramming untested"]},{"year":2024,"claim":"Characterized LRRC25 subcellular distribution and age/region-dependent brain expression, with elevation in Alzheimer's disease models and patient tissue, raising an associative CNS link.","evidence":"Immunoblot, immunofluorescence, subcellular fractionation in cell lines and mouse brain, AD model and human tissue comparison","pmids":["38476461"],"confidence":"Low","gaps":["Associative expression change without demonstrated functional consequence in AD","No causal manipulation of LRRC25 in neurodegeneration models"]},{"year":null,"claim":"How LRRC25 selects its diverse substrates (RIG-I, p65, G3BP1) and whether its transmembrane anchoring and a unifying biochemical activity govern adaptor specificity remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of LRRC25 or its substrate complexes","Determinants of substrate selectivity across pathways unknown","Role of membrane topology in adaptor function undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,5,6]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3]}],"complexes":[],"partners":["RIG-I","SQSTM1","RELA","ISG15","G3BP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N386","full_name":"Leucine-rich repeat-containing protein 25","aliases":["Monocyte and plasmacytoid-activated protein"],"length_aa":305,"mass_kda":33.2,"function":"Plays a role in the inhibition of RLR-mediated type I interferon signaling pathway by targeting RIGI for autophagic degradation. Interacts specifically with ISG15-associated RIGI to promote interaction between RIGI and the autophagic cargo receptor p62/SQSTM1 to mediate RIGI degradation via selective autophagy (PubMed:29288164). Also plays a role in the inhibition of NF-kappa-B signaling pathway and inflammatory response by promoting the degradation of p65/RELA","subcellular_location":"Membrane; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q8N386/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LRRC25","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LRRC25","total_profiled":1310},"omim":[{"mim_id":"607518","title":"LEUCINE-RICH REPEAT-CONTAINING PROTEIN 25; LRRC25","url":"https://www.omim.org/entry/607518"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Microtubules","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":31.0},{"tissue":"lymphoid tissue","ntpm":58.6}],"url":"https://www.proteinatlas.org/search/LRRC25"},"hgnc":{"alias_symbol":["MAPA","FLJ38116"],"prev_symbol":[]},"alphafold":{"accession":"Q8N386","domains":[{"cath_id":"3.80.10,3.80.10","chopping":"43-158","consensus_level":"high","plddt":92.8991,"start":43,"end":158}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N386","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N386-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N386-F1-predicted_aligned_error_v6.png","plddt_mean":70.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LRRC25","jax_strain_url":"https://www.jax.org/strain/search?query=LRRC25"},"sequence":{"accession":"Q8N386","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N386.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N386/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N386"}},"corpus_meta":[{"pmid":"29288164","id":"PMC_29288164","title":"LRRC25 inhibits type I 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Inhibitor of NF-κB Signaling Pathway by Promoting p65/RelA for Autophagic Degradation.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29044191","citation_count":53,"is_preprint":false},{"pmid":"31996428","id":"PMC_31996428","title":"Foot-and-Mouth Disease Virus 3A Protein Causes Upregulation of Autophagy-Related Protein LRRC25 To Inhibit the G3BP1-Mediated RIG-Like Helicase-Signaling Pathway.","date":"2020","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/31996428","citation_count":48,"is_preprint":false},{"pmid":"22709446","id":"PMC_22709446","title":"Effects of P-MAPA Immunomodulator on Toll-Like Receptors and p53: Potential Therapeutic Strategies for Infectious Diseases and Cancer.","date":"2012","source":"Infectious agents and cancer","url":"https://pubmed.ncbi.nlm.nih.gov/22709446","citation_count":35,"is_preprint":false},{"pmid":"27389279","id":"PMC_27389279","title":"Increased toll-like receptors and p53 levels regulate apoptosis and angiogenesis in non-muscle invasive bladder cancer: mechanism of action of P-MAPA biological response modifier.","date":"2016","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27389279","citation_count":31,"is_preprint":false},{"pmid":"32631946","id":"PMC_32631946","title":"MapA, a Second Large RTX Adhesin Conserved across the Pseudomonads, Contributes to Biofilm Formation by Pseudomonas fluorescens.","date":"2020","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/32631946","citation_count":26,"is_preprint":false},{"pmid":"24374021","id":"PMC_24374021","title":"Effects of P-MAPA immunomodulator on Toll-like receptor 2, ROS, nitric oxide, MAPKp38 and IKK in PBMC and macrophages from dogs with visceral leishmaniasis.","date":"2013","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24374021","citation_count":23,"is_preprint":false},{"pmid":"21563841","id":"PMC_21563841","title":"MAPA distinguishes 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PCC 6803.","date":"2009","source":"Microbiology (Reading, England)","url":"https://pubmed.ncbi.nlm.nih.gov/19359320","citation_count":2,"is_preprint":false},{"pmid":"38476461","id":"PMC_38476461","title":"LRRC25 expression during physiological aging and in mouse models of Alzheimer's disease and iPSC-derived neurons.","date":"2024","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/38476461","citation_count":1,"is_preprint":false},{"pmid":"40279244","id":"PMC_40279244","title":"Myeloid-lineage-specific membrane protein LRRC25 suppresses immunity in solid tumor and is a potential cancer immunotherapy checkpoint target.","date":"2025","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/40279244","citation_count":1,"is_preprint":false},{"pmid":"33299378","id":"PMC_33299378","title":"P-MAPA, a Fungi-Derived Immunomodulatory Compound, Induces a Proinflammatory Response in a Human Whole Blood Model.","date":"2020","source":"Mediators of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/33299378","citation_count":1,"is_preprint":false},{"pmid":"32484769","id":"PMC_32484769","title":"The P-MAPA Immunomodulator Partially Prevents Apoptosis Induced by Zika Virus Infection in THP-1 Cells.","date":"2021","source":"Current pharmaceutical biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/32484769","citation_count":1,"is_preprint":false},{"pmid":"31862453","id":"PMC_31862453","title":"P-mapa, a promisor immunomodulator against tumor cells of colonic tissues: An investigation of the action mechanism over the TLR4 signaling pathway.","date":"2019","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31862453","citation_count":1,"is_preprint":false},{"pmid":"37692278","id":"PMC_37692278","title":"Study effect of MAPA-VIP on control of allergic asthma pathophysiology.","date":"2023","source":"Postepy dermatologii i alergologii","url":"https://pubmed.ncbi.nlm.nih.gov/37692278","citation_count":0,"is_preprint":false},{"pmid":"40434066","id":"PMC_40434066","title":"S-MAPA: bridging the gap in psoriasis severity assessment.","date":"2025","source":"Dermatology reports","url":"https://pubmed.ncbi.nlm.nih.gov/40434066","citation_count":0,"is_preprint":false},{"pmid":"41853974","id":"PMC_41853974","title":"Inhibition of Aβ(40) peptide aggregation by Milk-derived Amyloid-like Protein Aggregates (MAPA).","date":"2026","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41853974","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.26.690778","title":"Improved Estimation of Correlation Accuracy for Machine Learning Brain-Phenotype Associations","date":"2025-12-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.26.690778","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.23.671949","title":"Leveraging Large Language Models for Redundancy-Aware Pathway Analysis and Deep Biological Interpretation","date":"2025-08-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.23.671949","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.31.667975","title":"Accelerated Discovery of Aptamer Beacons via Massively Parallel Screening","date":"2025-08-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.31.667975","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":24766,"output_tokens":2373,"usd":0.054947,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9487,"output_tokens":3148,"usd":0.063067,"stage2_stop_reason":"end_turn"},"total_usd":0.118014,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"LRRC25 specifically binds to ISG15-associated RIG-I upon RNA virus infection and promotes the interaction between RIG-I and the autophagic cargo receptor p62, mediating selective autophagic degradation of RIG-I to negatively regulate type I IFN signaling. Depletion of either LRRC25 or ISG15 abrogates the RIG-I–p62 interaction and autophagic degradation of RIG-I.\",\n      \"method\": \"Co-immunoprecipitation, knockdown/knockout loss-of-function, autophagic flux assays, RNA virus infection models\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic depletion of both LRRC25 and ISG15 with orthogonal phenotypic readouts, multiple mechanistic validations in one focused study\",\n      \"pmids\": [\"29288164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LRRC25 acts as a negative regulator of NF-κB signaling: its LRR domain directly interacts with the Rel Homology domain (RHD) of p65/RelA, enhances the interaction between p65/RelA and the autophagic cargo receptor p62, and thereby promotes autophagic degradation of p65/RelA. Knockout of LRRC25 potentiates NF-κB activation and inflammatory cytokine production.\",\n      \"method\": \"Ectopic overexpression, CRISPR/Cas9 knockout, domain-mapping Co-IP (LRR domain vs. RHD), autophagic degradation assays, cytokine measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping Co-IP, CRISPR knockout with defined phenotype, multiple orthogonal methods in one focused study\",\n      \"pmids\": [\"29044191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LRRC25 is a type I transmembrane molecule highly expressed in primary myeloid cells (granulocytes, monocytes) and is required for ATRA-induced terminal granulocytic differentiation; knockdown by siRNA/shRNA or knockout by CRISPR-Cas9 attenuates ATRA-induced differentiation, and restoration of LRRC25 in knockout cells rescues differentiation.\",\n      \"method\": \"siRNA/shRNA knockdown, CRISPR-Cas9 knockout, rescue experiments, flow cytometry for differentiation markers, subcellular localization analysis\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple loss-of-function approaches (siRNA, shRNA, CRISPR KO) with rescue, defined granulocytic differentiation phenotype, single lab but orthogonal methods\",\n      \"pmids\": [\"28536942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of LRRC25 in vivo accelerates pathological cardiac hypertrophy by promoting TGF-β1/Smad2/3 signaling and NF-κB activation; LRRC25 knockout mice show exacerbated cardiac fibrosis, dysfunction, and inflammation in response to aortic banding or angiotensin II stimulation, and inhibition of TGF-β1 or NF-κB abolishes the pro-hypertrophic effects of LRRC25 deficiency in vitro.\",\n      \"method\": \"LRRC25 knockout mouse model, aortic banding surgery, angiotensin II stimulation, western blot for phospho-Smad2/3, NF-κB activation assays, pharmacological inhibition\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo KO with defined cardiac phenotype and pathway inhibitor rescue, single lab, limited mechanistic resolution of direct binding\",\n      \"pmids\": [\"30340835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FMDV nonstructural protein 3A interacts with G3BP1 to upregulate LRRC25 expression, which then promotes autophagic degradation of G3BP1, thereby inhibiting G3BP1-mediated RIG-I/MDA5 (RLH) signaling and suppressing type I IFN responses. Similar effects were observed with 3A proteins from other picornaviruses (SVV, EV71, EMCV).\",\n      \"method\": \"Co-immunoprecipitation, overexpression of viral 3A proteins, siRNA knockdown, western blot, IFN reporter assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for 3A–G3BP1 interaction, LRRC25 overexpression/knockdown with defined IFN phenotype, replicated across multiple picornavirus 3A proteins, single lab\",\n      \"pmids\": [\"31996428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LRRC25 negatively regulates anti-tuberculosis immunity in microglia: silencing LRRC25 in BV2 cells infected with H37Rv (Mycobacterium tuberculosis) decreases the proportion of infected cells and significantly increases IFN-γ and ISG15 secretion, indicating that LRRC25 suppresses IFN-γ secretion and degrades free ISG15 in this context.\",\n      \"method\": \"siRNA knockdown of LRRC25 in BV2 microglia, H37Rv infection, ELISA for IFN-γ and ISG15, flow cytometry, qPCR, immunofluorescence\",\n      \"journal\": \"Microorganisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — siRNA loss-of-function with defined immunological phenotypes, single lab, single method per endpoint\",\n      \"pmids\": [\"37894158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LRRC25 is specifically expressed in myeloid cells including tumor-associated macrophages (TAMs); Lrrc25 deficiency in the tumor microenvironment reprograms TAMs toward an anti-tumor phenotype, elevates the Nox2-ROS-Nlrp3-IL1β pathway in TAMs, and enhances CD8+ T cell infiltration and activation to suppress tumor growth in multiple murine models.\",\n      \"method\": \"Lrrc25-deficient mouse models, multiple murine tumor models, TAM phenotyping, Nlrp3-IL1β pathway analysis, CD8+ T cell flow cytometry\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic KO with multiple tumor models, pathway identification (Nox2-ROS-Nlrp3-IL1β), defined immune cell phenotypes, single lab\",\n      \"pmids\": [\"40279244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LRRC25 protein is expressed in both cell membranes and cytoplasm in a punctate pattern in astrocytes, microglia, and neurons, and its expression is age- and brain-region-dependent in mice; LRRC25 protein levels are elevated in the cortex and hippocampus of two mouse models of Alzheimer's disease (APdeltaE9 and 3xTg) and in AD patient brains.\",\n      \"method\": \"Immunoblot, immunofluorescence, subcellular localization analysis in cell lines and mouse brain, comparison across AD mouse models and human tissue\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization established by immunofluorescence/fractionation but without direct functional consequence demonstrated; expression changes in AD models are associative\",\n      \"pmids\": [\"38476461\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LRRC25 is a type I transmembrane leucine-rich repeat protein expressed predominantly in myeloid cells that functions as a broad negative regulator of innate immune signaling: it acts as a secondary autophagic receptor by binding ISG15-modified RIG-I and bridging it to p62 for selective autophagic degradation (suppressing type I IFN responses), similarly promotes autophagic degradation of p65/RelA via its LRR–RHD interaction (suppressing NF-κB), is required for ATRA-induced granulocytic differentiation, regulates anti-tuberculosis IFN-γ secretion in microglia, and controls tumor-associated macrophage inflammatory programming through the Nox2-ROS-Nlrp3-IL1β axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LRRC25 is a type I transmembrane leucine-rich repeat protein expressed predominantly in myeloid cells that acts as a broad negative regulator of innate immune signaling by coupling immune effectors to selective autophagic degradation [#0, #2]. In antiviral signaling, LRRC25 binds ISG15-conjugated RIG-I and bridges it to the autophagic cargo receptor p62, driving selective autophagic turnover of RIG-I and dampening type I IFN responses; loss of either LRRC25 or ISG15 abolishes the RIG-I–p62 interaction [#0]. The same degradative logic applies to NF-\\u03baB signaling, where the LRR domain of LRRC25 directly engages the Rel Homology domain of p65/RelA and enhances its p62-dependent autophagic degradation, so that LRRC25 loss potentiates NF-\\u03baB activation and inflammatory cytokine output [#1]. Picornaviruses exploit this axis: viral 3A proteins acting through G3BP1 upregulate LRRC25, which then degrades G3BP1 to suppress RIG-I/MDA5 signaling and IFN induction [#4]. Beyond pathogen sensing, LRRC25 is required for ATRA-induced terminal granulocytic differentiation [#2], restrains anti-tuberculosis IFN-\\u03b3 secretion and free ISG15 in microglia [#5], and shapes tumor-associated macrophage programming, with its deficiency activating a Nox2-ROS-Nlrp3-IL1\\u03b2 axis that promotes anti-tumor immunity [#6]. In vivo, LRRC25 loss aggravates pathological cardiac hypertrophy through enhanced TGF-\\u03b21/Smad2/3 and NF-\\u03baB signaling [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established LRRC25 as a selective autophagy adaptor that terminates antiviral signaling by linking ISG15-modified RIG-I to p62 for degradation, answering how RIG-I is cleared to limit type I IFN.\",\n      \"evidence\": \"Reciprocal Co-IP, knockdown/knockout of LRRC25 and ISG15, autophagic flux assays in RNA virus infection models\",\n      \"pmids\": [\"29288164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ISG15-RIG-I recognition by LRRC25 not resolved\", \"Whether membrane anchoring is required for the bridging function untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed the same LRRC25-p62 degradative mechanism operates on NF-\\u03baB, with the LRR domain directly binding the p65/RelA RHD, defining a shared logic across two innate pathways.\",\n      \"evidence\": \"Domain-mapping Co-IP (LRR vs RHD), CRISPR/Cas9 knockout, autophagic degradation and cytokine assays\",\n      \"pmids\": [\"29044191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct LRR-RHD binding not validated by purified-protein reconstitution\", \"Selectivity for p65 over other Rel-family members not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified a developmental role distinct from immune suppression, showing LRRC25 is required for ATRA-induced granulocytic differentiation in myeloid cells.\",\n      \"evidence\": \"siRNA/shRNA knockdown, CRISPR-KO with rescue, flow cytometry for differentiation markers\",\n      \"pmids\": [\"28536942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between LRRC25 and the ATRA differentiation program unknown\", \"Whether the autophagy adaptor function underlies differentiation untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended LRRC25 function to cardiac pathology, showing its loss accelerates hypertrophy via TGF-\\u03b21/Smad2/3 and NF-\\u03baB, consistent with its role as a brake on inflammatory signaling.\",\n      \"evidence\": \"LRRC25 knockout mouse, aortic banding and angiotensin II models, phospho-Smad2/3 blots, pathway inhibitor rescue\",\n      \"pmids\": [\"30340835\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding partners in the TGF-\\u03b21/Smad pathway not mapped\", \"Cell type driving the cardiac phenotype not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed that picornaviruses co-opt LRRC25, with viral 3A proteins inducing it to degrade G3BP1 and suppress RLH signaling, expanding its substrate repertoire and showing pathogen exploitation.\",\n      \"evidence\": \"Co-IP, viral 3A overexpression, siRNA knockdown, IFN reporter assays across multiple picornaviruses\",\n      \"pmids\": [\"31996428\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether G3BP1 degradation uses the same p62-autophagy route as RIG-I not directly shown\", \"Mechanism of 3A-driven LRRC25 upregulation unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated LRRC25 restrains anti-tuberculosis immunity in microglia by suppressing IFN-\\u03b3 secretion and degrading free ISG15, extending its immunosuppressive role to CNS-resident myeloid cells.\",\n      \"evidence\": \"siRNA knockdown in BV2 microglia, H37Rv infection, ELISA for IFN-\\u03b3 and ISG15\",\n      \"pmids\": [\"37894158\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single loss-of-function method per endpoint without rescue\", \"Direct mechanism connecting LRRC25 to IFN-\\u03b3 control not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed LRRC25 deficiency reprograms tumor-associated macrophages toward anti-tumor activity via a Nox2-ROS-Nlrp3-IL1\\u03b2 axis, linking its myeloid expression to tumor immune control.\",\n      \"evidence\": \"Lrrc25-deficient mice, multiple murine tumor models, TAM phenotyping, CD8+ T cell flow cytometry\",\n      \"pmids\": [\"40279244\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target of LRRC25 within the Nox2-Nlrp3 axis not identified\", \"Whether autophagy adaptor activity drives TAM reprogramming untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Characterized LRRC25 subcellular distribution and age/region-dependent brain expression, with elevation in Alzheimer's disease models and patient tissue, raising an associative CNS link.\",\n      \"evidence\": \"Immunoblot, immunofluorescence, subcellular fractionation in cell lines and mouse brain, AD model and human tissue comparison\",\n      \"pmids\": [\"38476461\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Associative expression change without demonstrated functional consequence in AD\", \"No causal manipulation of LRRC25 in neurodegeneration models\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LRRC25 selects its diverse substrates (RIG-I, p65, G3BP1) and whether its transmembrane anchoring and a unifying biochemical activity govern adaptor specificity remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of LRRC25 or its substrate complexes\", \"Determinants of substrate selectivity across pathways unknown\", \"Role of membrane topology in adaptor function undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 5, 6]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RIG-I\", \"SQSTM1\", \"RELA\", \"ISG15\", \"G3BP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}