{"gene":"TG_235140","gene_symbol":"NSM","run_date":"2026-09-08T12:58:24","timeline":{"discoveries":[{"year":2021,"finding":"TgNSM is a bradyzoite-stage secreted effector that localizes to the host cell nucleus and co-opts the NCoR/SMRT transcriptional repressor complex to inhibit IFN-driven expression of PKR and MLKL, thereby blocking necroptosis and protecting the parasite's intracellular cyst niche during chronic infection.","method":"Genetic analysis of secreted effectors localizing to the host nucleus; functional epistasis with TgIST; measurement of PKR and MLKL expression; necroptosis assays in infected cells","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Moderate — nuclear localization established by direct imaging, NCoR/SMRT targeting and functional inhibition of necroptosis confirmed by epistasis with TgIST and downstream readouts (PKR, MLKL expression, cell death), single lab but multiple orthogonal methods","pmids":["34043960"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2026,"finding":"TgNSM acts as one of eight MYR1-dependent dense granule effectors that cooperatively activate the non-canonical NF-κB pathway (RelB/p52) in host cells; no single effector is solely responsible, indicating an additive network mechanism. Activation involves TRAF3 depletion, NIK stabilization, p100 phosphorylation, and p52 processing.","method":"Combinatorial knockout parasite panel; nuclear accumulation assays for RelB and p52; Western blot for TRAF3, NIK, p100/p52; MYR1-dependent export dependency confirmed genetically","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — combinatorial KO panel with multiple pathway readouts in a single lab; preprint, not yet peer-reviewed","pmids":["41959509"],"is_preprint":true,"attribution":[{"species":"Toxoplasma gondii","strain":"Type I"},{"species":"Toxoplasma gondii","strain":"Type II"}]},{"year":2025,"finding":"NSM protein abundance increases during in vitro culture adaptation of T. gondii field isolates, correlating with increased virulence factor expression, as measured by label-free LC-MS proteomics.","method":"Label-free liquid chromatography-mass spectrometry proteomics comparing low- and high-passage isolates","journal":"Frontiers in cellular and infection microbiology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — expression-level proteomics only, no direct mechanistic experiment on NSM function","pmids":["41036225"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":"Type II"},{"species":"Toxoplasma gondii","strain":"Type III"}]}],"current_model":"TgNSM is a bradyzoite-stage secreted effector exported via the MYR1 pathway into the host cell nucleus, where it co-opts the NCoR/SMRT transcriptional repressor complex to suppress IFN-driven expression of PKR and MLKL (thereby blocking necroptosis and protecting intracellular cysts), and also participates—redundantly with seven other MYR1-dependent effectors—in activating the non-canonical NF-κB pathway through TRAF3 depletion and NIK stabilization."},"narrative":{"mechanistic_narrative":"TgNSM is a bradyzoite-stage secreted dense granule effector of Toxoplasma gondii that is exported into the host cell and traffics to the host nucleus, where it manipulates host transcription to sustain the chronic infection niche [PMID:34043960]. In the nucleus it co-opts the NCoR/SMRT transcriptional repressor complex to suppress IFN-driven expression of PKR and MLKL, thereby blocking necroptosis and protecting the parasite's intracellular cyst [PMID:34043960]. TgNSM additionally functions as one of eight MYR1-dependent effectors that cooperatively activate the non-canonical NF-κB pathway (RelB/p52) in host cells through TRAF3 depletion, NIK stabilization, and p100 processing, an additive network mechanism in which no single effector is solely responsible [PMID:41959509]. Beyond these host-manipulation roles, no further mechanistic detail on TgNSM has been characterized in the available corpus.","teleology":[{"year":2021,"claim":"Established that TgNSM is a nuclear-targeted secreted effector whose function is to protect the chronic cyst by silencing host necroptosis, answering how the bradyzoite stage evades IFN-driven cell death.","evidence":"Genetic analysis of nucleus-localizing secreted effectors, epistasis with TgIST, and PKR/MLKL expression plus necroptosis assays in infected cells","pmids":["34043960"],"confidence":"High","gaps":["Mechanism by which TgNSM engages NCoR/SMRT (direct binding vs. bridging) not resolved","Route of nuclear import and export machinery not defined in this finding","Whether IFN-independent targets exist is unaddressed"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2025,"claim":"Correlated NSM protein abundance with culture adaptation and virulence factor expression, hinting that NSM levels track the parasite's virulent state but without testing function.","evidence":"Label-free LC-MS proteomics comparing low- and high-passage field isolates","pmids":["41036225"],"confidence":"Low","gaps":["Expression-correlation only; no direct mechanistic test of NSM function","Causal link between NSM abundance and virulence not established","Does not distinguish cause from consequence of adaptation"],"attribution":[{"species":"Toxoplasma gondii","strain":"Type II"},{"species":"Toxoplasma gondii","strain":"Type III"}]},{"year":2026,"claim":"Placed TgNSM within a redundant network of eight MYR1-dependent effectors that additively activate non-canonical NF-κB, clarifying that NSM's role in this pathway is cooperative rather than singular.","evidence":"Combinatorial knockout parasite panel with RelB/p52 nuclear accumulation assays and Western blots for TRAF3, NIK, and p100/p52 (preprint)","pmids":["41959509"],"confidence":"Medium","gaps":["Individual contribution of NSM cannot be isolated from the other seven effectors","Direct molecular target of NSM in the TRAF3/NIK axis unknown","Preprint, not yet peer-reviewed"],"attribution":[{"species":"Toxoplasma gondii","strain":"Type I"},{"species":"Toxoplasma gondii","strain":"Type II"}]},{"year":null,"claim":"How TgNSM physically engages the NCoR/SMRT complex and whether its necroptosis-blocking and NF-κB-activating activities are mechanistically linked remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or biochemical map of the NSM–NCoR/SMRT interaction","No direct molecular target within the non-canonical NF-κB machinery","Relationship between the two host-manipulation activities undefined"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Host NCoR/SMRT transcriptional repressor complex (co-opted by TgNSM)"],"partners":["NCOR/SMRT COMPLEX","MYR1 (EXPORT DEPENDENCY)","TGIST (FUNCTIONAL EPISTASIS)"],"other_free_text":["Bradyzoite-stage secreted dense granule effector protecting the chronic cyst niche","Suppresses IFN-driven PKR and MLKL expression to block necroptosis","One of eight MYR1-dependent effectors additively activating RelB/p52 non-canonical NF-κB via TRAF3 depletion and NIK stabilization","Protein abundance increases with in vitro culture adaptation of field isolates"]},"strain_conflicts":[]},"prefetch_data":{},"corpus_meta":[{"pmid":"34043960","id":"PMC_34043960","title":"Toxoplasma gondii secreted effectors co-opt host repressor complexes to inhibit necroptosis.","date":"2021","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/34043960","citation_count":68,"is_preprint":false},{"pmid":"39597646","id":"PMC_39597646","title":"IL-36 Gamma: A Novel Adjuvant Cytokine Enhancing Protective Immunity Induced by DNA Immunization with TGIST and TGNSM Against Toxoplasma gondii Infection in Mice.","date":"2024","source":"Microorganisms","url":"https://pubmed.ncbi.nlm.nih.gov/39597646","citation_count":8,"is_preprint":false},{"pmid":"41036225","id":"PMC_41036225","title":"Proteome changes during in vitro culture adaptation of Toxoplasma gondii archetypal II and III field isolates.","date":"2025","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/41036225","citation_count":1,"is_preprint":false},{"pmid":"41959509","id":"PMC_41959509","title":"A Suite of Eight Toxoplasma gondii Effectors Cooperates to Activate the Non-canonical NF-κB Pathway.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41959509","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4533,"output_tokens":992,"usd":0.01424,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5878,"output_tokens":2192,"usd":0.042095,"stage2_stop_reason":"end_turn"},"total_usd":0.056335,"stage1_batch_id":"msgbatch_01TEPNZ4MCzJ7xtsNwosiDRk","stage2_batch_id":"msgbatch_01FQShM7n1sfCr4pWTDShmki","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"TgNSM is a bradyzoite-stage secreted effector that localizes to the host cell nucleus and co-opts the NCoR/SMRT transcriptional repressor complex to inhibit IFN-driven expression of PKR and MLKL, thereby blocking necroptosis and protecting the parasite's intracellular cyst niche during chronic infection.\",\n      \"method\": \"Genetic analysis of secreted effectors localizing to the host nucleus; functional epistasis with TgIST; measurement of PKR and MLKL expression; necroptosis assays in infected cells\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — nuclear localization established by direct imaging, NCoR/SMRT targeting and functional inhibition of necroptosis confirmed by epistasis with TgIST and downstream readouts (PKR, MLKL expression, cell death), single lab but multiple orthogonal methods\",\n      \"pmids\": [\"34043960\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TgNSM acts as one of eight MYR1-dependent dense granule effectors that cooperatively activate the non-canonical NF-κB pathway (RelB/p52) in host cells; no single effector is solely responsible, indicating an additive network mechanism. Activation involves TRAF3 depletion, NIK stabilization, p100 phosphorylation, and p52 processing.\",\n      \"method\": \"Combinatorial knockout parasite panel; nuclear accumulation assays for RelB and p52; Western blot for TRAF3, NIK, p100/p52; MYR1-dependent export dependency confirmed genetically\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — combinatorial KO panel with multiple pathway readouts in a single lab; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"41959509\"],\n      \"is_preprint\": true,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"Type I\"},\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"Type II\"}\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NSM protein abundance increases during in vitro culture adaptation of T. gondii field isolates, correlating with increased virulence factor expression, as measured by label-free LC-MS proteomics.\",\n      \"method\": \"Label-free liquid chromatography-mass spectrometry proteomics comparing low- and high-passage isolates\",\n      \"journal\": \"Frontiers in cellular and infection microbiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — expression-level proteomics only, no direct mechanistic experiment on NSM function\",\n      \"pmids\": [\"41036225\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"Type II\"},\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"Type III\"}\n      ]\n    }\n  ],\n  \"current_model\": \"TgNSM is a bradyzoite-stage secreted effector exported via the MYR1 pathway into the host cell nucleus, where it co-opts the NCoR/SMRT transcriptional repressor complex to suppress IFN-driven expression of PKR and MLKL (thereby blocking necroptosis and protecting intracellular cysts), and also participates—redundantly with seven other MYR1-dependent effectors—in activating the non-canonical NF-κB pathway through TRAF3 depletion and NIK stabilization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TgNSM is a bradyzoite-stage secreted dense granule effector of Toxoplasma gondii that is exported into the host cell and traffics to the host nucleus, where it manipulates host transcription to sustain the chronic infection niche [#0]. In the nucleus it co-opts the NCoR/SMRT transcriptional repressor complex to suppress IFN-driven expression of PKR and MLKL, thereby blocking necroptosis and protecting the parasite's intracellular cyst [#0]. TgNSM additionally functions as one of eight MYR1-dependent effectors that cooperatively activate the non-canonical NF-\\u03baB pathway (RelB/p52) in host cells through TRAF3 depletion, NIK stabilization, and p100 processing, an additive network mechanism in which no single effector is solely responsible [#1]. Beyond these host-manipulation roles, no further mechanistic detail on TgNSM has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Established that TgNSM is a nuclear-targeted secreted effector whose function is to protect the chronic cyst by silencing host necroptosis, answering how the bradyzoite stage evades IFN-driven cell death.\",\n      \"evidence\": \"Genetic analysis of nucleus-localizing secreted effectors, epistasis with TgIST, and PKR/MLKL expression plus necroptosis assays in infected cells\",\n      \"pmids\": [\"34043960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which TgNSM engages NCoR/SMRT (direct binding vs. bridging) not resolved\", \"Route of nuclear import and export machinery not defined in this finding\", \"Whether IFN-independent targets exist is unaddressed\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Correlated NSM protein abundance with culture adaptation and virulence factor expression, hinting that NSM levels track the parasite's virulent state but without testing function.\",\n      \"evidence\": \"Label-free LC-MS proteomics comparing low- and high-passage field isolates\",\n      \"pmids\": [\"41036225\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Expression-correlation only; no direct mechanistic test of NSM function\", \"Causal link between NSM abundance and virulence not established\", \"Does not distinguish cause from consequence of adaptation\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"Type II\"}, {\"species\": \"Toxoplasma gondii\", \"strain\": \"Type III\"}]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placed TgNSM within a redundant network of eight MYR1-dependent effectors that additively activate non-canonical NF-\\u03baB, clarifying that NSM's role in this pathway is cooperative rather than singular.\",\n      \"evidence\": \"Combinatorial knockout parasite panel with RelB/p52 nuclear accumulation assays and Western blots for TRAF3, NIK, and p100/p52 (preprint)\",\n      \"pmids\": [\"41959509\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Individual contribution of NSM cannot be isolated from the other seven effectors\", \"Direct molecular target of NSM in the TRAF3/NIK axis unknown\", \"Preprint, not yet peer-reviewed\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"Type I\"}, {\"species\": \"Toxoplasma gondii\", \"strain\": \"Type II\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TgNSM physically engages the NCoR/SMRT complex and whether its necroptosis-blocking and NF-\\u03baB-activating activities are mechanistically linked remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural or biochemical map of the NSM\\u2013NCoR/SMRT interaction\", \"No direct molecular target within the non-canonical NF-\\u03baB machinery\", \"Relationship between the two host-manipulation activities undefined\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140105\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0140677\", \"supporting_discovery_ids\": [0, 1], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0044167\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0060545\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0038061\", \"supporting_discovery_ids\": [1], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"Type I\"}, {\"species\": \"Toxoplasma gondii\", \"strain\": \"Type II\"}]}\n    ],\n    \"complexes\": [\n      \"Host NCoR/SMRT transcriptional repressor complex (co-opted by TgNSM)\"\n    ],\n    \"partners\": [\n      \"NCoR/SMRT complex\",\n      \"MYR1 (export dependency)\",\n      \"TgIST (functional epistasis)\"\n    ],\n    \"other_free_text\": [\n      \"Bradyzoite-stage secreted dense granule effector protecting the chronic cyst niche\",\n      \"Suppresses IFN-driven PKR and MLKL expression to block necroptosis\",\n      \"One of eight MYR1-dependent effectors additively activating RelB/p52 non-canonical NF-\\u03baB via TRAF3 depletion and NIK stabilization\",\n      \"Protein abundance increases with in vitro culture adaptation of field isolates\"\n    ]\n  },\n  \"strain_conflicts\": []\n}","audit_flag":null,"strains":[{"strain":"ME49","gene_id":"TGME49_235140","name":"NSM","product":"secreted effector protein NSM","uniprot_acc":"S8EWJ6","chromosome":"TGME49_chrX","start_pos":4633594},{"strain":"GT1","gene_id":"TGGT1_235140","name":null,"product":"hypothetical protein","uniprot_acc":null,"chromosome":"TGGT1_chrX","start_pos":4531283},{"strain":"RH88","gene_id":"TGRH88_042200","name":null,"product":"unspecified product","uniprot_acc":null,"chromosome":"CM023091","start_pos":2905596},{"strain":"VEG","gene_id":"TGVEG_235140","name":null,"product":"hypothetical protein","uniprot_acc":"V4ZAB4","chromosome":"TGVEG_chrX","start_pos":4547903}]}