{"gene":"NLRP11","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2017,"finding":"NLRP11 inhibits TLR signalling by recruiting the ubiquitin ligase RNF19A to catalyze K48-linked ubiquitination of TRAF6 at multiple sites, leading to proteasomal degradation of TRAF6 and consequent attenuation of NF-κB and MAPK signalling and proinflammatory cytokine production. Deficiency of either NLRP11 or RNF19A abrogates K48-linked ubiquitination and degradation of TRAF6.","method":"Co-immunoprecipitation, ubiquitination assays, knockdown/knockout with NF-κB/MAPK and cytokine readouts","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assays, and loss-of-function experiments with defined molecular and cellular phenotypes; replicated across multiple approaches in one rigorous study","pmids":["29215004"],"is_preprint":false},{"year":2017,"finding":"Upon viral infection, NLRP11 is induced by type I IFN and translocates to mitochondria where it interacts with MAVS. Using MAVS as a platform, NLRP11 degrades TRAF6 to attenuate type I IFN production and virus-induced apoptosis, thereby disrupting the MAVS signalosome.","method":"Co-immunoprecipitation, subcellular fractionation/localization, knockdown with IFN and apoptosis readouts","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and localization experiments with functional consequence (IFN and apoptosis), single lab, multiple methods","pmids":["29097393"],"is_preprint":false},{"year":2021,"finding":"NLRP11 binds the RNA helicase DDX3X via its LRR domain (mapped by Co-IP and domain-deletion analysis). NLRP11 abolishes IKKε-mediated phosphorylation of DDX3X, reducing type I IFN induction upon viral infection. NLRP11 also suppresses NLRP3-mediated caspase-1 activation in an LRR domain-dependent manner, suggesting DDX3X sequestration as the mechanism.","method":"Co-immunoprecipitation, LC-MS/MS, domain-deletion mutants, phosphorylation assays, caspase-1 activation assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirmed by LC-MS/MS, domain mapping, and functional phosphorylation assays; single lab, multiple orthogonal methods","pmids":["34054816"],"is_preprint":false},{"year":2022,"finding":"NLRP11 is an essential component of the NLRP3 inflammasome in human macrophages. NLRP11 interacts with both NLRP3 and ASC; deletion of NLRP11 prevents inflammasome assembly, NLRP3 and ASC polymerization, caspase-1 activation, pyroptosis, and cytokine release specifically downstream of NLRP3 (not other inflammasomes). Restoration of NLRP11 lacking the PYRIN domain (PYD) fails to rescue inflammasome activation, demonstrating the PYD is required. NLRP11 is also required for inflammasome responses driven by CAPS-associated NLRP3 mutations.","method":"CRISPR knockout, Co-immunoprecipitation, ASC polymerization assays, caspase-1 activation assays, pyroptosis readouts, cytokine measurement, domain-deletion rescue experiments","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO with multiple orthogonal phenotypic readouts, domain-rescue experiments, reciprocal Co-IP; single lab but highly rigorous with multiple independent methods","pmids":["35624206"],"is_preprint":false},{"year":2020,"finding":"Adenosine stimulation induces NLRP11 expression in B lymphoblasts, leading to interaction of NLRP11 with the ASC adaptor protein in a manner that does not activate caspase-1. NLRP11-expressing cells suppress CD4+ T helper cell IFN-γ and IL-17A production in an inflammasome-independent manner; siRNA knockdown of NLRP11 recovers IFN-γ and IL-17A.","method":"siRNA knockdown, co-immunoprecipitation (endogenous NLRP11–ASC), caspase-1 activity assay, co-culture T cell cytokine assays","journal":"Journal of immunology research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP, siRNA rescue, and co-culture functional readouts; multiple methods but single lab and partial mechanistic resolution","pmids":["32832566"],"is_preprint":false},{"year":2023,"finding":"NLRP11 is a primate-specific cytosolic pattern recognition receptor for LPS in human macrophages. NLRP11 directly binds LPS and separately binds caspase-4, forming a high-molecular-weight complex with caspase-4 in HEK293T cells. NLRP11 is required for efficient caspase-4 inflammasome activation during intracellular Gram-negative bacterial infection or electroporation of LPS.","method":"CRISPR knockout, LPS binding assay, co-immunoprecipitation (NLRP11–caspase-4 complex), size-exclusion/gel-filtration, infection and electroporation functional assays","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO, direct LPS binding assay, Co-IP of NLRP11–caspase-4 complex, multiple functional readouts; single lab but multiple orthogonal methods in one rigorous study","pmids":["37478192"],"is_preprint":false},{"year":2023,"finding":"NLRP11 bridges the histone acetyltransferase KAT7 to vimentin, promoting KAT7-mediated acetylation of vimentin at Lys104 (K104Ac). NLRP11 binds both KAT7 and vimentin; NLRP11 also induces cytoplasmic localization of KAT7. This modification promotes EMT and malignant behavior of vimentin-positive lung adenocarcinoma cells in vitro and in vivo.","method":"Co-immunoprecipitation, acetylation assays, subcellular localization (fractionation/imaging), vimentin-K104Q acetylation-mimetic transfection, in vitro and in vivo tumor assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, acetylation assays with site-specific mutant, localization experiments, and functional in vivo/in vitro assays; single lab, multiple methods","pmids":["37424170"],"is_preprint":false},{"year":2025,"finding":"The NACHT and LRR domains of NLRP11, but not its PYD, are required for NLRP3 canonical inflammasome activation and caspase-4 non-canonical inflammasome activation during Shigella flexneri infection in human macrophages. NLRP11 is also required for non-canonical (caspase-4/5-dependent) inflammasome activation during Mycobacterium tuberculosis and M. kansasii infection, extending NLRP11 pathogen recognition beyond Gram-negative LPS-containing bacteria.","method":"CRISPR-defined domain deletion mutants (NLRP11 ΔNACHT/ΔLRR and ΔPYD), caspase-4 activation assays, NLRP3 inflammasome activation readouts, bacterial infection models","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined domain-deletion mutants with multiple independent functional readouts across distinct bacterial pathogens; published in peer-reviewed journal with rigorous domain dissection","pmids":["40272180"],"is_preprint":false},{"year":2026,"finding":"NLRP11 functions upstream of caspase-4 (CASP4), forming an ASC-independent complex that requires a conserved CASP4 p20 residue. NLRP11 binds cytosolic LPS and enhances CASP4-dependent LPS recognition, promoting gasdermin-D activation and pyroptosis. Mutational analyses show that CASP4 interaction with NLRP11, LPS binding, and CASP4 catalytic activity are each required for efficient pyroptosis in human macrophages.","method":"Mutational analysis, co-immunoprecipitation, LPS binding assays, caspase-4 activation and pyroptosis assays (gasdermin-D cleavage), ASC-deficient cell experiments","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mutants, binding assays, and functional readouts; preprint (not yet peer-reviewed), single lab","pmids":["41676729"],"is_preprint":true}],"current_model":"NLRP11 is a primate-specific innate immune regulator that functions in multiple distinct pathways: (1) it recruits E3 ubiquitin ligase RNF19A to catalyze K48-linked polyubiquitination and proteasomal degradation of TRAF6, thereby attenuating TLR and MAVS signaling and type I IFN/NF-κB responses; (2) it acts as a cytosolic pattern recognition receptor for LPS and additional microbial products, forming an ASC-independent complex with caspase-4 via its NACHT/LRR domains to drive non-canonical inflammasome activation and pyroptosis; (3) its PYD domain is required for interaction with NLRP3 and ASC to enable canonical NLRP3 inflammasome assembly, caspase-1 activation, and IL-1β/IL-18 release in human macrophages; and (4) through its LRR domain it sequesters DDX3X to suppress IKKε-mediated phosphorylation and downstream type I IFN induction, and also bridges KAT7 to vimentin to promote K104 acetylation and EMT in cancer cells."},"narrative":{"mechanistic_narrative":"NLRP11 is a primate-specific NLR-family protein that operates at the interface of innate immune signaling, acting both as a negative regulator of antiviral/inflammatory signaling and as a positive sensor and scaffold for inflammasome assembly [PMID:29215004, PMID:35624206, PMID:37478192]. As a brake on signaling, NLRP11 recruits the E3 ubiquitin ligase RNF19A to drive K48-linked polyubiquitination and proteasomal degradation of TRAF6, attenuating NF-κB and MAPK output and proinflammatory cytokine production [PMID:29215004]; upon viral infection it is induced by type I IFN, translocates to mitochondria, and uses MAVS as a platform to degrade TRAF6 and dampen type I IFN responses [PMID:29097393]. Through its LRR domain it binds the RNA helicase DDX3X and blocks IKKε-mediated DDX3X phosphorylation, providing a second route to suppress type I IFN induction [PMID:34054816]. In a contrasting positive role, NLRP11 is an essential component of the human NLRP3 inflammasome, interacting with NLRP3 and ASC through a PYD-dependent mechanism required for inflammasome assembly, caspase-1 activation, pyroptosis, and IL-1β/IL-18 release [PMID:35624206]. NLRP11 additionally functions as a cytosolic pattern-recognition receptor that directly binds LPS and assembles an ASC-independent complex with caspase-4 to drive non-canonical inflammasome activation, gasdermin-D cleavage, and pyroptosis during intracellular Gram-negative and mycobacterial infection, a function dependent on its NACHT and LRR domains rather than its PYD [PMID:37478192, PMID:40272180, PMID:41676729]. Beyond immunity, NLRP11 bridges the acetyltransferase KAT7 to vimentin to promote vimentin K104 acetylation and epithelial-mesenchymal transition in lung adenocarcinoma [PMID:37424170].","teleology":[{"year":2017,"claim":"Established that NLRP11 is a negative regulator of innate immune signaling by defining how it triggers degradation of a central signaling hub.","evidence":"Co-IP, ubiquitination assays, and knockdown/knockout with NF-κB/MAPK and cytokine readouts showing NLRP11 recruits RNF19A to drive K48-linked ubiquitination and proteasomal degradation of TRAF6","pmids":["29215004"],"confidence":"High","gaps":["Does not define which upstream stimuli engage the NLRP11–RNF19A module","Structural basis of TRAF6 selection not resolved"]},{"year":2017,"claim":"Extended the negative-regulatory role to antiviral signaling by localizing NLRP11 to a specific platform.","evidence":"Co-IP, subcellular fractionation, and knockdown with IFN/apoptosis readouts showing IFN-induced NLRP11 translocates to mitochondria, binds MAVS, and degrades TRAF6 to limit type I IFN","pmids":["29097393"],"confidence":"Medium","gaps":["Mechanism of mitochondrial translocation unknown","Relationship to the RNF19A-mediated TRAF6 degradation pathway not integrated"]},{"year":2020,"claim":"Identified an inflammasome-independent immunosuppressive function in B lymphoblasts, broadening NLRP11 roles beyond classical inflammasome biology.","evidence":"siRNA knockdown, endogenous NLRP11–ASC Co-IP, caspase-1 activity assay, and T cell co-culture cytokine assays showing adenosine-induced NLRP11 binds ASC without activating caspase-1 and suppresses Th cytokines","pmids":["32832566"],"confidence":"Medium","gaps":["Molecular basis of T cell suppression not defined","How NLRP11–ASC binding avoids caspase-1 activation unresolved"]},{"year":2021,"claim":"Mapped a second IFN-suppressive mechanism via direct interaction with a helicase, and linked the LRR domain to inflammasome control.","evidence":"Co-IP, LC-MS/MS, domain-deletion mutants, phosphorylation and caspase-1 assays showing LRR-dependent binding of DDX3X that blocks IKKε-mediated DDX3X phosphorylation and dampens NLRP3-driven caspase-1 activation","pmids":["34054816"],"confidence":"Medium","gaps":["DDX3X sequestration model not directly demonstrated","Reconciliation with NLRP11's positive role in NLRP3 inflammasome unresolved"]},{"year":2022,"claim":"Reframed NLRP11 as an essential positive component of the human NLRP3 inflammasome, identifying the domain required.","evidence":"CRISPR knockout, reciprocal Co-IP, ASC polymerization, caspase-1 and pyroptosis assays, and PYD-deletion rescue showing PYD-dependent interaction with NLRP3 and ASC is required for inflammasome assembly","pmids":["35624206"],"confidence":"High","gaps":["Does not reconcile the positive NLRP3 role with the earlier suppressive findings","Structural detail of the NLRP11–NLRP3–ASC complex absent"]},{"year":2023,"claim":"Defined NLRP11 as a cytosolic LPS sensor that initiates non-canonical inflammasome activation via caspase-4.","evidence":"CRISPR knockout, direct LPS binding assay, Co-IP and gel-filtration of an NLRP11–caspase-4 complex, plus infection/electroporation functional assays in human macrophages","pmids":["37478192"],"confidence":"High","gaps":["Stoichiometry and architecture of the NLRP11–caspase-4 complex not solved","How LPS binding triggers complex assembly unclear"]},{"year":2023,"claim":"Uncovered a non-immune oncogenic function as a scaffold linking an acetyltransferase to a cytoskeletal substrate.","evidence":"Co-IP, site-specific acetylation assays with K104Q mimetic, localization, and in vitro/in vivo tumor assays showing NLRP11 bridges KAT7 to vimentin to promote K104 acetylation and EMT","pmids":["37424170"],"confidence":"Medium","gaps":["Whether the EMT function relates to immune signaling domains not addressed","Regulation of KAT7 cytoplasmic relocalization by NLRP11 unresolved"]},{"year":2025,"claim":"Dissected the domain requirements distinguishing canonical from non-canonical inflammasome roles and broadened pathogen scope.","evidence":"CRISPR-defined ΔNACHT/ΔLRR and ΔPYD mutants with caspase-4 and NLRP3 activation readouts across Shigella, M. tuberculosis, and M. kansasii infection","pmids":["40272180"],"confidence":"High","gaps":["Apparent discrepancy with PYD-dependence reported for NLRP3 activation not fully reconciled","Ligand recognized in mycobacteria not identified"]},{"year":2026,"claim":"Resolved the molecular requirements for NLRP11-driven non-canonical pyroptosis at the level of caspase-4 contacts and catalysis.","evidence":"Mutational analysis, Co-IP, LPS binding, and gasdermin-D cleavage/pyroptosis assays in ASC-deficient cells showing a conserved CASP4 p20 residue, NLRP11–CASP4 binding, LPS binding, and CASP4 catalysis are each required (preprint)","pmids":["41676729"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Structural model of the NLRP11–CASP4 interface not determined"]},{"year":null,"claim":"How NLRP11's opposing roles—TRAF6/IFN suppression versus inflammasome promotion—are switched within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model integrates the negative signaling-regulator and positive inflammasome-sensor functions","No structural data for any NLRP11 complex","Determinants of stimulus- or cell-type-specific pathway choice unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[5,8]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[5,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,5,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,6]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,3,5,7]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,5,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2]}],"complexes":["NLRP3 inflammasome","NLRP11–caspase-4 non-canonical inflammasome complex"],"partners":["TRAF6","RNF19A","MAVS","DDX3X","NLRP3","ASC","CASP4","KAT7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P59045","full_name":"NACHT, LRR and PYD domains-containing protein 11","aliases":["Nucleotide-binding oligomerization domain protein 17","PAAD-and NACHT domain-containing protein 10","PYRIN-containing APAF1-like protein 6"],"length_aa":1033,"mass_kda":117.8,"function":"Involved in inflammation","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P59045/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NLRP11","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/NLRP11","total_profiled":1310},"omim":[{"mim_id":"609664","title":"NLR FAMILY, PYRIN DOMAIN-CONTAINING 11; NLRP11","url":"https://www.omim.org/entry/609664"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"epididymis","ntpm":1.1},{"tissue":"liver","ntpm":1.0}],"url":"https://www.proteinatlas.org/search/NLRP11"},"hgnc":{"alias_symbol":["PYPAF6","NOD17","PAN10","CLR19.6"],"prev_symbol":["NALP11"]},"alphafold":{"accession":"P59045","domains":[{"cath_id":"-","chopping":"12-78","consensus_level":"high","plddt":83.2134,"start":12,"end":78},{"cath_id":"3.40.50,3.40.50","chopping":"112-300","consensus_level":"high","plddt":84.294,"start":112,"end":300},{"cath_id":"-","chopping":"382-516","consensus_level":"medium","plddt":85.0733,"start":382,"end":516},{"cath_id":"3.80.10","chopping":"519-605_613-692","consensus_level":"medium","plddt":87.9204,"start":519,"end":692},{"cath_id":"3.80.10.10","chopping":"846-991","consensus_level":"medium","plddt":91.7039,"start":846,"end":991},{"cath_id":"1.10.8","chopping":"301-365","consensus_level":"medium","plddt":89.5238,"start":301,"end":365}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P59045","model_url":"https://alphafold.ebi.ac.uk/files/AF-P59045-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P59045-F1-predicted_aligned_error_v6.png","plddt_mean":85.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NLRP11","jax_strain_url":"https://www.jax.org/strain/search?query=NLRP11"},"sequence":{"accession":"P59045","fasta_url":"https://rest.uniprot.org/uniprotkb/P59045.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P59045/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P59045"}},"corpus_meta":[{"pmid":"29215004","id":"PMC_29215004","title":"NLRP11 attenuates Toll-like receptor signalling by targeting TRAF6 for degradation via the ubiquitin ligase RNF19A.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29215004","citation_count":72,"is_preprint":false},{"pmid":"35624206","id":"PMC_35624206","title":"NLRP3 licenses NLRP11 for inflammasome activation in human macrophages.","date":"2022","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35624206","citation_count":48,"is_preprint":false},{"pmid":"34054816","id":"PMC_34054816","title":"DDX3X Links NLRP11 to the Regulation of Type I Interferon Responses and NLRP3 Inflammasome Activation.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34054816","citation_count":34,"is_preprint":false},{"pmid":"29097393","id":"PMC_29097393","title":"NLRP11 disrupts MAVS signalosome to inhibit type I interferon signaling and virus-induced apoptosis.","date":"2017","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/29097393","citation_count":29,"is_preprint":false},{"pmid":"37478192","id":"PMC_37478192","title":"NLRP11 is a pattern recognition receptor for bacterial lipopolysaccharide in the cytosol of human macrophages.","date":"2023","source":"Science immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37478192","citation_count":24,"is_preprint":false},{"pmid":"37424170","id":"PMC_37424170","title":"The NLRP11 Protein Bridges the Histone Lysine Acetyltransferase KAT7 to Acetylate Vimentin in the Early Stage of Lung Adenocarcinoma.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37424170","citation_count":19,"is_preprint":false},{"pmid":"32832566","id":"PMC_32832566","title":"Adenosine-Induced NLRP11 in B Lymphoblasts Suppresses Human CD4+ T Helper Cell Responses.","date":"2020","source":"Journal of immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/32832566","citation_count":11,"is_preprint":false},{"pmid":"40272180","id":"PMC_40272180","title":"NLRP11 is required for canonical NLRP3 and non-canonical inflammasome activation during human macrophage infection with mycobacteria.","date":"2025","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/40272180","citation_count":3,"is_preprint":false},{"pmid":"40093077","id":"PMC_40093077","title":"NLRP11 is required for canonical NLRP3 and non-canonical inflammasome activation during human macrophage infection with mycobacteria.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40093077","citation_count":1,"is_preprint":false},{"pmid":"41676729","id":"PMC_41676729","title":"NLRP11 promotes non-canonical inflammasome activation in human macrophages by enhancing caspase-4 recognition of cytosolic lipopolysaccharide.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41676729","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7269,"output_tokens":2901,"usd":0.032661,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10107,"output_tokens":3710,"usd":0.071642,"stage2_stop_reason":"end_turn"},"total_usd":0.104303,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"NLRP11 inhibits TLR signalling by recruiting the ubiquitin ligase RNF19A to catalyze K48-linked ubiquitination of TRAF6 at multiple sites, leading to proteasomal degradation of TRAF6 and consequent attenuation of NF-κB and MAPK signalling and proinflammatory cytokine production. Deficiency of either NLRP11 or RNF19A abrogates K48-linked ubiquitination and degradation of TRAF6.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, knockdown/knockout with NF-κB/MAPK and cytokine readouts\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assays, and loss-of-function experiments with defined molecular and cellular phenotypes; replicated across multiple approaches in one rigorous study\",\n      \"pmids\": [\"29215004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Upon viral infection, NLRP11 is induced by type I IFN and translocates to mitochondria where it interacts with MAVS. Using MAVS as a platform, NLRP11 degrades TRAF6 to attenuate type I IFN production and virus-induced apoptosis, thereby disrupting the MAVS signalosome.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation/localization, knockdown with IFN and apoptosis readouts\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and localization experiments with functional consequence (IFN and apoptosis), single lab, multiple methods\",\n      \"pmids\": [\"29097393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NLRP11 binds the RNA helicase DDX3X via its LRR domain (mapped by Co-IP and domain-deletion analysis). NLRP11 abolishes IKKε-mediated phosphorylation of DDX3X, reducing type I IFN induction upon viral infection. NLRP11 also suppresses NLRP3-mediated caspase-1 activation in an LRR domain-dependent manner, suggesting DDX3X sequestration as the mechanism.\",\n      \"method\": \"Co-immunoprecipitation, LC-MS/MS, domain-deletion mutants, phosphorylation assays, caspase-1 activation assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirmed by LC-MS/MS, domain mapping, and functional phosphorylation assays; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34054816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NLRP11 is an essential component of the NLRP3 inflammasome in human macrophages. NLRP11 interacts with both NLRP3 and ASC; deletion of NLRP11 prevents inflammasome assembly, NLRP3 and ASC polymerization, caspase-1 activation, pyroptosis, and cytokine release specifically downstream of NLRP3 (not other inflammasomes). Restoration of NLRP11 lacking the PYRIN domain (PYD) fails to rescue inflammasome activation, demonstrating the PYD is required. NLRP11 is also required for inflammasome responses driven by CAPS-associated NLRP3 mutations.\",\n      \"method\": \"CRISPR knockout, Co-immunoprecipitation, ASC polymerization assays, caspase-1 activation assays, pyroptosis readouts, cytokine measurement, domain-deletion rescue experiments\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO with multiple orthogonal phenotypic readouts, domain-rescue experiments, reciprocal Co-IP; single lab but highly rigorous with multiple independent methods\",\n      \"pmids\": [\"35624206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Adenosine stimulation induces NLRP11 expression in B lymphoblasts, leading to interaction of NLRP11 with the ASC adaptor protein in a manner that does not activate caspase-1. NLRP11-expressing cells suppress CD4+ T helper cell IFN-γ and IL-17A production in an inflammasome-independent manner; siRNA knockdown of NLRP11 recovers IFN-γ and IL-17A.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation (endogenous NLRP11–ASC), caspase-1 activity assay, co-culture T cell cytokine assays\",\n      \"journal\": \"Journal of immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP, siRNA rescue, and co-culture functional readouts; multiple methods but single lab and partial mechanistic resolution\",\n      \"pmids\": [\"32832566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NLRP11 is a primate-specific cytosolic pattern recognition receptor for LPS in human macrophages. NLRP11 directly binds LPS and separately binds caspase-4, forming a high-molecular-weight complex with caspase-4 in HEK293T cells. NLRP11 is required for efficient caspase-4 inflammasome activation during intracellular Gram-negative bacterial infection or electroporation of LPS.\",\n      \"method\": \"CRISPR knockout, LPS binding assay, co-immunoprecipitation (NLRP11–caspase-4 complex), size-exclusion/gel-filtration, infection and electroporation functional assays\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO, direct LPS binding assay, Co-IP of NLRP11–caspase-4 complex, multiple functional readouts; single lab but multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"37478192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NLRP11 bridges the histone acetyltransferase KAT7 to vimentin, promoting KAT7-mediated acetylation of vimentin at Lys104 (K104Ac). NLRP11 binds both KAT7 and vimentin; NLRP11 also induces cytoplasmic localization of KAT7. This modification promotes EMT and malignant behavior of vimentin-positive lung adenocarcinoma cells in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, acetylation assays, subcellular localization (fractionation/imaging), vimentin-K104Q acetylation-mimetic transfection, in vitro and in vivo tumor assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, acetylation assays with site-specific mutant, localization experiments, and functional in vivo/in vitro assays; single lab, multiple methods\",\n      \"pmids\": [\"37424170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The NACHT and LRR domains of NLRP11, but not its PYD, are required for NLRP3 canonical inflammasome activation and caspase-4 non-canonical inflammasome activation during Shigella flexneri infection in human macrophages. NLRP11 is also required for non-canonical (caspase-4/5-dependent) inflammasome activation during Mycobacterium tuberculosis and M. kansasii infection, extending NLRP11 pathogen recognition beyond Gram-negative LPS-containing bacteria.\",\n      \"method\": \"CRISPR-defined domain deletion mutants (NLRP11 ΔNACHT/ΔLRR and ΔPYD), caspase-4 activation assays, NLRP3 inflammasome activation readouts, bacterial infection models\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined domain-deletion mutants with multiple independent functional readouts across distinct bacterial pathogens; published in peer-reviewed journal with rigorous domain dissection\",\n      \"pmids\": [\"40272180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NLRP11 functions upstream of caspase-4 (CASP4), forming an ASC-independent complex that requires a conserved CASP4 p20 residue. NLRP11 binds cytosolic LPS and enhances CASP4-dependent LPS recognition, promoting gasdermin-D activation and pyroptosis. Mutational analyses show that CASP4 interaction with NLRP11, LPS binding, and CASP4 catalytic activity are each required for efficient pyroptosis in human macrophages.\",\n      \"method\": \"Mutational analysis, co-immunoprecipitation, LPS binding assays, caspase-4 activation and pyroptosis assays (gasdermin-D cleavage), ASC-deficient cell experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mutants, binding assays, and functional readouts; preprint (not yet peer-reviewed), single lab\",\n      \"pmids\": [\"41676729\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"NLRP11 is a primate-specific innate immune regulator that functions in multiple distinct pathways: (1) it recruits E3 ubiquitin ligase RNF19A to catalyze K48-linked polyubiquitination and proteasomal degradation of TRAF6, thereby attenuating TLR and MAVS signaling and type I IFN/NF-κB responses; (2) it acts as a cytosolic pattern recognition receptor for LPS and additional microbial products, forming an ASC-independent complex with caspase-4 via its NACHT/LRR domains to drive non-canonical inflammasome activation and pyroptosis; (3) its PYD domain is required for interaction with NLRP3 and ASC to enable canonical NLRP3 inflammasome assembly, caspase-1 activation, and IL-1β/IL-18 release in human macrophages; and (4) through its LRR domain it sequesters DDX3X to suppress IKKε-mediated phosphorylation and downstream type I IFN induction, and also bridges KAT7 to vimentin to promote K104 acetylation and EMT in cancer cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NLRP11 is a primate-specific NLR-family protein that operates at the interface of innate immune signaling, acting both as a negative regulator of antiviral/inflammatory signaling and as a positive sensor and scaffold for inflammasome assembly [#0, #3, #5]. As a brake on signaling, NLRP11 recruits the E3 ubiquitin ligase RNF19A to drive K48-linked polyubiquitination and proteasomal degradation of TRAF6, attenuating NF-\\u03baB and MAPK output and proinflammatory cytokine production [#0]; upon viral infection it is induced by type I IFN, translocates to mitochondria, and uses MAVS as a platform to degrade TRAF6 and dampen type I IFN responses [#1]. Through its LRR domain it binds the RNA helicase DDX3X and blocks IKK\\u03b5-mediated DDX3X phosphorylation, providing a second route to suppress type I IFN induction [#2]. In a contrasting positive role, NLRP11 is an essential component of the human NLRP3 inflammasome, interacting with NLRP3 and ASC through a PYD-dependent mechanism required for inflammasome assembly, caspase-1 activation, pyroptosis, and IL-1\\u03b2/IL-18 release [#3]. NLRP11 additionally functions as a cytosolic pattern-recognition receptor that directly binds LPS and assembles an ASC-independent complex with caspase-4 to drive non-canonical inflammasome activation, gasdermin-D cleavage, and pyroptosis during intracellular Gram-negative and mycobacterial infection, a function dependent on its NACHT and LRR domains rather than its PYD [#5, #7, #8]. Beyond immunity, NLRP11 bridges the acetyltransferase KAT7 to vimentin to promote vimentin K104 acetylation and epithelial-mesenchymal transition in lung adenocarcinoma [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that NLRP11 is a negative regulator of innate immune signaling by defining how it triggers degradation of a central signaling hub.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, and knockdown/knockout with NF-\\u03baB/MAPK and cytokine readouts showing NLRP11 recruits RNF19A to drive K48-linked ubiquitination and proteasomal degradation of TRAF6\",\n      \"pmids\": [\"29215004\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define which upstream stimuli engage the NLRP11\\u2013RNF19A module\", \"Structural basis of TRAF6 selection not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended the negative-regulatory role to antiviral signaling by localizing NLRP11 to a specific platform.\",\n      \"evidence\": \"Co-IP, subcellular fractionation, and knockdown with IFN/apoptosis readouts showing IFN-induced NLRP11 translocates to mitochondria, binds MAVS, and degrades TRAF6 to limit type I IFN\",\n      \"pmids\": [\"29097393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of mitochondrial translocation unknown\", \"Relationship to the RNF19A-mediated TRAF6 degradation pathway not integrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified an inflammasome-independent immunosuppressive function in B lymphoblasts, broadening NLRP11 roles beyond classical inflammasome biology.\",\n      \"evidence\": \"siRNA knockdown, endogenous NLRP11\\u2013ASC Co-IP, caspase-1 activity assay, and T cell co-culture cytokine assays showing adenosine-induced NLRP11 binds ASC without activating caspase-1 and suppresses Th cytokines\",\n      \"pmids\": [\"32832566\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of T cell suppression not defined\", \"How NLRP11\\u2013ASC binding avoids caspase-1 activation unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped a second IFN-suppressive mechanism via direct interaction with a helicase, and linked the LRR domain to inflammasome control.\",\n      \"evidence\": \"Co-IP, LC-MS/MS, domain-deletion mutants, phosphorylation and caspase-1 assays showing LRR-dependent binding of DDX3X that blocks IKK\\u03b5-mediated DDX3X phosphorylation and dampens NLRP3-driven caspase-1 activation\",\n      \"pmids\": [\"34054816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DDX3X sequestration model not directly demonstrated\", \"Reconciliation with NLRP11's positive role in NLRP3 inflammasome unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reframed NLRP11 as an essential positive component of the human NLRP3 inflammasome, identifying the domain required.\",\n      \"evidence\": \"CRISPR knockout, reciprocal Co-IP, ASC polymerization, caspase-1 and pyroptosis assays, and PYD-deletion rescue showing PYD-dependent interaction with NLRP3 and ASC is required for inflammasome assembly\",\n      \"pmids\": [\"35624206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not reconcile the positive NLRP3 role with the earlier suppressive findings\", \"Structural detail of the NLRP11\\u2013NLRP3\\u2013ASC complex absent\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined NLRP11 as a cytosolic LPS sensor that initiates non-canonical inflammasome activation via caspase-4.\",\n      \"evidence\": \"CRISPR knockout, direct LPS binding assay, Co-IP and gel-filtration of an NLRP11\\u2013caspase-4 complex, plus infection/electroporation functional assays in human macrophages\",\n      \"pmids\": [\"37478192\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and architecture of the NLRP11\\u2013caspase-4 complex not solved\", \"How LPS binding triggers complex assembly unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered a non-immune oncogenic function as a scaffold linking an acetyltransferase to a cytoskeletal substrate.\",\n      \"evidence\": \"Co-IP, site-specific acetylation assays with K104Q mimetic, localization, and in vitro/in vivo tumor assays showing NLRP11 bridges KAT7 to vimentin to promote K104 acetylation and EMT\",\n      \"pmids\": [\"37424170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the EMT function relates to immune signaling domains not addressed\", \"Regulation of KAT7 cytoplasmic relocalization by NLRP11 unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Dissected the domain requirements distinguishing canonical from non-canonical inflammasome roles and broadened pathogen scope.\",\n      \"evidence\": \"CRISPR-defined \\u0394NACHT/\\u0394LRR and \\u0394PYD mutants with caspase-4 and NLRP3 activation readouts across Shigella, M. tuberculosis, and M. kansasii infection\",\n      \"pmids\": [\"40272180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Apparent discrepancy with PYD-dependence reported for NLRP3 activation not fully reconciled\", \"Ligand recognized in mycobacteria not identified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved the molecular requirements for NLRP11-driven non-canonical pyroptosis at the level of caspase-4 contacts and catalysis.\",\n      \"evidence\": \"Mutational analysis, Co-IP, LPS binding, and gasdermin-D cleavage/pyroptosis assays in ASC-deficient cells showing a conserved CASP4 p20 residue, NLRP11\\u2013CASP4 binding, LPS binding, and CASP4 catalysis are each required (preprint)\",\n      \"pmids\": [\"41676729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Structural model of the NLRP11\\u2013CASP4 interface not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NLRP11's opposing roles\\u2014TRAF6/IFN suppression versus inflammasome promotion\\u2014are switched within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model integrates the negative signaling-regulator and positive inflammasome-sensor functions\", \"No structural data for any NLRP11 complex\", \"Determinants of stimulus- or cell-type-specific pathway choice unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 5, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 3, 5, 7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 5, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [\n      \"NLRP3 inflammasome\",\n      \"NLRP11\\u2013caspase-4 non-canonical inflammasome complex\"\n    ],\n    \"partners\": [\n      \"TRAF6\",\n      \"RNF19A\",\n      \"MAVS\",\n      \"DDX3X\",\n      \"NLRP3\",\n      \"ASC\",\n      \"CASP4\",\n      \"KAT7\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}