{"gene":"SBK2","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":2022,"finding":"SBK2 (Sbk2) is a muscle-specific, atrium-enriched serine/threonine protein kinase that localizes around the A-band of cardiac sarcomeres in neonatal and adult rats. Knockdown of Sbk2 in neonatal rat atrial myocytes (NRAMs), conditionally immortalized atrial myocytes (iAMs), and their human counterparts caused loss of sarcomeric organization, accompanied by decreased sarcomeric gene expression at both the transcriptome and proteome levels. Co-immunoprecipitation using Sbk2 as bait identified interaction partners involved in translation, intracellular trafficking, cytoskeletal organization, chromatin modification, and sarcomere formation.","method":"Knockdown (loss-of-function) with sarcomeric organization as phenotypic readout; transcriptome and proteome analysis; co-immunoprecipitation; subcellular localization by immunofluorescence","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, KD with defined cellular phenotype, transcriptome + proteome, single lab with multiple orthogonal methods","pmids":["35587025"],"is_preprint":false},{"year":2026,"finding":"SBK2 directly binds and phosphorylates NDUFV1 (NADH:ubiquinone oxidoreductase core subunit V1) at serine 251. This phosphorylation enhances the interaction between NDUFV1 and the cytosolic chaperone HSPA1A and facilitates TOM70-dependent mitochondrial import of NDUFV1. Increased mitochondrial NDUFV1 promotes complex I activity, respiratory supercomplex assembly, oxidative phosphorylation, mitochondrial fusion, and redox homeostasis. Cardiomyocyte-specific SBK2 overexpression attenuated cardiac hypertrophy, fibrosis, and improved systolic function, while SBK2 knockdown exacerbated these phenotypes. A phospho-deficient NDUFV1 mutant (S251A) failed to rescue hypertrophic phenotypes in SBK2-deficient cardiomyocytes, confirming the necessity of this phosphorylation event.","method":"In vitro kinase assay; co-immunoprecipitation; proteomic and interactome analyses; biochemical fractionation; blue native PAGE; loss- and gain-of-function studies in cardiomyocytes and mice; phospho-deficient mutant rescue experiment","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with site-specific mutagenesis (S251A rescue), co-IP, biochemical fractionation, and in vivo KO/OE with defined phenotypes, multiple orthogonal methods in a single rigorous study","pmids":["42153297"],"is_preprint":false},{"year":2026,"finding":"SBK2 phosphorylates NLRP3 at Ser161 in macrophages, triggering Tollip-dependent autophagic degradation of the inflammasome component and subsequent inflammasome inactivation. Macrophage-specific SBK2 knockout exacerbated atherosclerotic plaque formation and inflammatory responses, while macrophage-targeted SBK2 overexpression attenuated disease progression. SBK2 is described as the sole known protein kinase capable of mediating selective autophagic clearance of NLRP3. Pharmacological activation of SBK2 with rebaudioside N suppressed NLRP3-mediated IL-1β/IL-18 secretion, and these effects were abolished in SBK2-deficient models.","method":"In vitro kinase activity assay; co-immunoprecipitation; mass spectrometry; macrophage-specific knockout and overexpression in mice; single-cell sequencing; pharmacological rescue abolished in KO","journal":"European heart journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay identifying phosphorylation site, co-IP, MS, macrophage-specific KO/OE with defined phenotypes, pharmacological rescue abolished in KO (multiple orthogonal methods, single lab)","pmids":["41684124"],"is_preprint":false},{"year":2026,"finding":"SBK2 is downregulated in multiple desmin-related cardiomyopathy (DRC) mouse models compared to non-transgenic controls, as confirmed by RT-qPCR and western blotting, suggesting a conserved role for SBK2 in proteotoxic cardiac disease progression.","method":"RT-qPCR and western blotting in multiple DRC mouse models","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — expression change confirmed by western blot and qPCR in disease models, but no direct mechanistic experiment performed on SBK2 function in this study","pmids":["41653366"],"is_preprint":false}],"current_model":"SBK2 (SH3 domain-binding kinase 2) is a cardiac-enriched serine/threonine kinase that maintains sarcomere integrity in atrial cardiomyocytes, phosphorylates NDUFV1 at Ser251 to facilitate its TOM70-dependent mitochondrial import and complex I activity (thereby restraining pathological cardiac hypertrophy), and phosphorylates NLRP3 at Ser161 in macrophages to trigger Tollip-dependent autophagic degradation of the inflammasome, thereby suppressing inflammatory responses and atherosclerosis."},"narrative":{"mechanistic_narrative":"SBK2 (SH3 domain-binding kinase 2) is a muscle-specific, atrium-enriched serine/threonine protein kinase that maintains sarcomere integrity and restrains cardiac and inflammatory pathology through site-specific substrate phosphorylation [PMID:35587025, PMID:42153297]. In atrial cardiomyocytes it localizes around the A-band of the sarcomere, and its loss disrupts sarcomeric organization and downregulates sarcomeric gene expression at both transcript and protein levels [PMID:35587025]. SBK2 directly binds and phosphorylates the complex I subunit NDUFV1 at Ser251, which strengthens NDUFV1 association with the cytosolic chaperone HSPA1A and drives TOM70-dependent mitochondrial import; the resulting rise in mitochondrial NDUFV1 promotes complex I activity, respiratory supercomplex assembly, oxidative phosphorylation, and redox homeostasis, with cardiomyocyte SBK2 overexpression attenuating hypertrophy and a phospho-deficient NDUFV1-S251A mutant failing to rescue SBK2-deficient cells [PMID:42153297]. In macrophages, SBK2 phosphorylates NLRP3 at Ser161 to trigger Tollip-dependent autophagic degradation of the inflammasome, and macrophage-specific SBK2 loss exacerbates atherosclerotic plaque formation while its activation suppresses IL-1β/IL-18 secretion [PMID:41684124].","teleology":[{"year":2022,"claim":"Established SBK2 as a sarcomere-associated cardiac kinase by showing it is required for atrial sarcomere structure, answering whether this kinase has a defined cellular role in cardiomyocytes.","evidence":"Knockdown in rat and human atrial myocytes with sarcomeric organization, transcriptome/proteome, immunofluorescence localization, and reciprocal Co-IP","pmids":["35587025"],"confidence":"Medium","gaps":["No direct kinase substrate identified in this study","Co-IP partners were not validated as direct phosphorylation targets","Mechanism linking SBK2 to sarcomeric gene expression unresolved"]},{"year":2026,"claim":"Identified NDUFV1-Ser251 as a direct SBK2 substrate, mechanistically connecting the kinase to mitochondrial complex I import and protection against cardiac hypertrophy.","evidence":"In vitro kinase assay with S251A mutagenesis, biochemical fractionation, blue native PAGE, and in vivo loss/gain-of-function with phospho-deficient rescue in mice","pmids":["42153297"],"confidence":"High","gaps":["How SBK2 kinase activity itself is regulated is unknown","Whether the same axis operates outside cardiomyocytes is not addressed","Structural basis of NDUFV1 recognition not determined"]},{"year":2026,"claim":"Extended SBK2 function to innate immunity by showing it phosphorylates NLRP3-Ser161 to drive Tollip-dependent autophagic inflammasome clearance, linking the kinase to atherosclerosis control.","evidence":"In vitro kinase assay, Co-IP, mass spectrometry, macrophage-specific KO/OE in mice, single-cell sequencing, and pharmacological rescue (rebaudioside N) abolished in KO","pmids":["41684124"],"confidence":"High","gaps":["How Ser161 phosphorylation mechanistically recruits Tollip is not detailed","Relationship between the cardiac and macrophage SBK2 functions unexplored","Endogenous activator of SBK2 in macrophages unknown"]},{"year":2026,"claim":"Associated SBK2 with proteotoxic cardiac disease by documenting its downregulation in desmin-related cardiomyopathy models, raising the question of whether loss of SBK2 contributes to disease progression.","evidence":"RT-qPCR and western blotting in multiple DRC mouse models","pmids":["41653366"],"confidence":"Low","gaps":["Expression correlation only; no functional manipulation of SBK2 in this disease context","Causal contribution of SBK2 loss to DRC not tested","No substrate or pathway implicated in this model"]},{"year":null,"claim":"How SBK2 kinase activity is regulated upstream and how its sarcomeric, mitochondrial, and inflammasome functions are coordinated remain open.","evidence":"","pmids":[],"confidence":"Low","gaps":["No upstream activator or signaling input identified","No structural model of the kinase","Unclear whether sarcomere maintenance is direct or downstream of metabolic effects"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[0]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2]}],"complexes":[],"partners":["NDUFV1","HSPA1A","TOM70","NLRP3","TOLLIP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P0C263","full_name":"Serine/threonine-protein kinase SBK2","aliases":["SH3 domain-binding kinase family member 2","Sugen kinase 69","SgK069"],"length_aa":348,"mass_kda":38.1,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P0C263/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SBK2","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SBK2","total_profiled":1310},"omim":[{"mim_id":"620414","title":"SH3 DOMAIN-BINDING KINASE FAMILY, MEMBER 2; SBK2","url":"https://www.omim.org/entry/620414"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"heart muscle","ntpm":122.0}],"url":"https://www.proteinatlas.org/search/SBK2"},"hgnc":{"alias_symbol":["SGK069"],"prev_symbol":[]},"alphafold":{"accession":"P0C263","domains":[{"cath_id":"3.30.200.20","chopping":"47-138","consensus_level":"high","plddt":95.9215,"start":47,"end":138},{"cath_id":"1.10.510.10","chopping":"144-344","consensus_level":"high","plddt":92.6603,"start":144,"end":344}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P0C263","model_url":"https://alphafold.ebi.ac.uk/files/AF-P0C263-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P0C263-F1-predicted_aligned_error_v6.png","plddt_mean":89.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SBK2","jax_strain_url":"https://www.jax.org/strain/search?query=SBK2"},"sequence":{"accession":"P0C263","fasta_url":"https://rest.uniprot.org/uniprotkb/P0C263.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P0C263/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P0C263"}},"corpus_meta":[{"pmid":"22987116","id":"PMC_22987116","title":"Single cell molecular recognition of migrating and invading tumor cells using a targeted fluorescent probe to receptor PTPmu.","date":"2012","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/22987116","citation_count":19,"is_preprint":false},{"pmid":"35587025","id":"PMC_35587025","title":"Sbk2, a Newly Discovered Atrium-Enriched Regulator of Sarcomere Integrity.","date":"2022","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/35587025","citation_count":14,"is_preprint":false},{"pmid":"23730413","id":"PMC_23730413","title":"Molecular Magnetic Resonance Imaging of Tumors with a PTPµ Targeted Contrast Agent.","date":"2013","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/23730413","citation_count":13,"is_preprint":false},{"pmid":"26435847","id":"PMC_26435847","title":"Molecular Imaging of Tumors Using a Quantitative T 1 Mapping Technique via Magnetic Resonance Imaging.","date":"2015","source":"Diagnostics (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/26435847","citation_count":12,"is_preprint":false},{"pmid":"39871147","id":"PMC_39871147","title":"Transcriptome analysis of muscle atrophy in Leizhou black goats: identification of key genes and insights into limb-girdle muscular dystrophy.","date":"2025","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/39871147","citation_count":7,"is_preprint":false},{"pmid":"39222219","id":"PMC_39222219","title":"Isolation of Monocrotophos degrading bacterial consortium from agricultural soil for in vivo analysis of pesticide degradation.","date":"2024","source":"Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology]","url":"https://pubmed.ncbi.nlm.nih.gov/39222219","citation_count":2,"is_preprint":false},{"pmid":"41684124","id":"PMC_41684124","title":"Macrophage SBK2 suppresses inflammation and atherosclerosis by NLRP3 phosphorylation.","date":"2026","source":"European heart journal","url":"https://pubmed.ncbi.nlm.nih.gov/41684124","citation_count":1,"is_preprint":false},{"pmid":"36695968","id":"PMC_36695968","title":"Comparison of Near-Infrared Imaging Agents Targeting the PTPmu Tumor Biomarker.","date":"2023","source":"Molecular imaging and biology","url":"https://pubmed.ncbi.nlm.nih.gov/36695968","citation_count":1,"is_preprint":false},{"pmid":"42153297","id":"PMC_42153297","title":"SBK2-Driven NDUFV1 Phosphorylation and Translocation Limits Cardiac Hypertrophy.","date":"2026","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/42153297","citation_count":0,"is_preprint":false},{"pmid":"41610137","id":"PMC_41610137","title":"Aberrant skeletal muscle morphogenesis and myofiber differentiation characterize equine myotonic dystrophy.","date":"2026","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/41610137","citation_count":0,"is_preprint":false},{"pmid":"41653366","id":"PMC_41653366","title":"Transcriptome remodeling of mouse hearts during postnatal cardiac maturation and under proteotoxic stress.","date":"2026","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/41653366","citation_count":0,"is_preprint":false},{"pmid":"34642452","id":"PMC_34642452","title":"Pet ownership in pregnancy and methylation pattern in cord blood.","date":"2021","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/34642452","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9785,"output_tokens":1517,"usd":0.026055,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8247,"output_tokens":2128,"usd":0.047218,"stage2_stop_reason":"end_turn"},"total_usd":0.073273,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"SBK2 (Sbk2) is a muscle-specific, atrium-enriched serine/threonine protein kinase that localizes around the A-band of cardiac sarcomeres in neonatal and adult rats. Knockdown of Sbk2 in neonatal rat atrial myocytes (NRAMs), conditionally immortalized atrial myocytes (iAMs), and their human counterparts caused loss of sarcomeric organization, accompanied by decreased sarcomeric gene expression at both the transcriptome and proteome levels. Co-immunoprecipitation using Sbk2 as bait identified interaction partners involved in translation, intracellular trafficking, cytoskeletal organization, chromatin modification, and sarcomere formation.\",\n      \"method\": \"Knockdown (loss-of-function) with sarcomeric organization as phenotypic readout; transcriptome and proteome analysis; co-immunoprecipitation; subcellular localization by immunofluorescence\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, KD with defined cellular phenotype, transcriptome + proteome, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35587025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SBK2 directly binds and phosphorylates NDUFV1 (NADH:ubiquinone oxidoreductase core subunit V1) at serine 251. This phosphorylation enhances the interaction between NDUFV1 and the cytosolic chaperone HSPA1A and facilitates TOM70-dependent mitochondrial import of NDUFV1. Increased mitochondrial NDUFV1 promotes complex I activity, respiratory supercomplex assembly, oxidative phosphorylation, mitochondrial fusion, and redox homeostasis. Cardiomyocyte-specific SBK2 overexpression attenuated cardiac hypertrophy, fibrosis, and improved systolic function, while SBK2 knockdown exacerbated these phenotypes. A phospho-deficient NDUFV1 mutant (S251A) failed to rescue hypertrophic phenotypes in SBK2-deficient cardiomyocytes, confirming the necessity of this phosphorylation event.\",\n      \"method\": \"In vitro kinase assay; co-immunoprecipitation; proteomic and interactome analyses; biochemical fractionation; blue native PAGE; loss- and gain-of-function studies in cardiomyocytes and mice; phospho-deficient mutant rescue experiment\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with site-specific mutagenesis (S251A rescue), co-IP, biochemical fractionation, and in vivo KO/OE with defined phenotypes, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"42153297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SBK2 phosphorylates NLRP3 at Ser161 in macrophages, triggering Tollip-dependent autophagic degradation of the inflammasome component and subsequent inflammasome inactivation. Macrophage-specific SBK2 knockout exacerbated atherosclerotic plaque formation and inflammatory responses, while macrophage-targeted SBK2 overexpression attenuated disease progression. SBK2 is described as the sole known protein kinase capable of mediating selective autophagic clearance of NLRP3. Pharmacological activation of SBK2 with rebaudioside N suppressed NLRP3-mediated IL-1β/IL-18 secretion, and these effects were abolished in SBK2-deficient models.\",\n      \"method\": \"In vitro kinase activity assay; co-immunoprecipitation; mass spectrometry; macrophage-specific knockout and overexpression in mice; single-cell sequencing; pharmacological rescue abolished in KO\",\n      \"journal\": \"European heart journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay identifying phosphorylation site, co-IP, MS, macrophage-specific KO/OE with defined phenotypes, pharmacological rescue abolished in KO (multiple orthogonal methods, single lab)\",\n      \"pmids\": [\"41684124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SBK2 is downregulated in multiple desmin-related cardiomyopathy (DRC) mouse models compared to non-transgenic controls, as confirmed by RT-qPCR and western blotting, suggesting a conserved role for SBK2 in proteotoxic cardiac disease progression.\",\n      \"method\": \"RT-qPCR and western blotting in multiple DRC mouse models\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — expression change confirmed by western blot and qPCR in disease models, but no direct mechanistic experiment performed on SBK2 function in this study\",\n      \"pmids\": [\"41653366\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SBK2 (SH3 domain-binding kinase 2) is a cardiac-enriched serine/threonine kinase that maintains sarcomere integrity in atrial cardiomyocytes, phosphorylates NDUFV1 at Ser251 to facilitate its TOM70-dependent mitochondrial import and complex I activity (thereby restraining pathological cardiac hypertrophy), and phosphorylates NLRP3 at Ser161 in macrophages to trigger Tollip-dependent autophagic degradation of the inflammasome, thereby suppressing inflammatory responses and atherosclerosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SBK2 (SH3 domain-binding kinase 2) is a muscle-specific, atrium-enriched serine/threonine protein kinase that maintains sarcomere integrity and restrains cardiac and inflammatory pathology through site-specific substrate phosphorylation [#0, #1]. In atrial cardiomyocytes it localizes around the A-band of the sarcomere, and its loss disrupts sarcomeric organization and downregulates sarcomeric gene expression at both transcript and protein levels [#0]. SBK2 directly binds and phosphorylates the complex I subunit NDUFV1 at Ser251, which strengthens NDUFV1 association with the cytosolic chaperone HSPA1A and drives TOM70-dependent mitochondrial import; the resulting rise in mitochondrial NDUFV1 promotes complex I activity, respiratory supercomplex assembly, oxidative phosphorylation, and redox homeostasis, with cardiomyocyte SBK2 overexpression attenuating hypertrophy and a phospho-deficient NDUFV1-S251A mutant failing to rescue SBK2-deficient cells [#1]. In macrophages, SBK2 phosphorylates NLRP3 at Ser161 to trigger Tollip-dependent autophagic degradation of the inflammasome, and macrophage-specific SBK2 loss exacerbates atherosclerotic plaque formation while its activation suppresses IL-1\\u03b2/IL-18 secretion [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2022,\n      \"claim\": \"Established SBK2 as a sarcomere-associated cardiac kinase by showing it is required for atrial sarcomere structure, answering whether this kinase has a defined cellular role in cardiomyocytes.\",\n      \"evidence\": \"Knockdown in rat and human atrial myocytes with sarcomeric organization, transcriptome/proteome, immunofluorescence localization, and reciprocal Co-IP\",\n      \"pmids\": [\"35587025\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct kinase substrate identified in this study\",\n        \"Co-IP partners were not validated as direct phosphorylation targets\",\n        \"Mechanism linking SBK2 to sarcomeric gene expression unresolved\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified NDUFV1-Ser251 as a direct SBK2 substrate, mechanistically connecting the kinase to mitochondrial complex I import and protection against cardiac hypertrophy.\",\n      \"evidence\": \"In vitro kinase assay with S251A mutagenesis, biochemical fractionation, blue native PAGE, and in vivo loss/gain-of-function with phospho-deficient rescue in mice\",\n      \"pmids\": [\"42153297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How SBK2 kinase activity itself is regulated is unknown\",\n        \"Whether the same axis operates outside cardiomyocytes is not addressed\",\n        \"Structural basis of NDUFV1 recognition not determined\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended SBK2 function to innate immunity by showing it phosphorylates NLRP3-Ser161 to drive Tollip-dependent autophagic inflammasome clearance, linking the kinase to atherosclerosis control.\",\n      \"evidence\": \"In vitro kinase assay, Co-IP, mass spectrometry, macrophage-specific KO/OE in mice, single-cell sequencing, and pharmacological rescue (rebaudioside N) abolished in KO\",\n      \"pmids\": [\"41684124\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How Ser161 phosphorylation mechanistically recruits Tollip is not detailed\",\n        \"Relationship between the cardiac and macrophage SBK2 functions unexplored\",\n        \"Endogenous activator of SBK2 in macrophages unknown\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Associated SBK2 with proteotoxic cardiac disease by documenting its downregulation in desmin-related cardiomyopathy models, raising the question of whether loss of SBK2 contributes to disease progression.\",\n      \"evidence\": \"RT-qPCR and western blotting in multiple DRC mouse models\",\n      \"pmids\": [\"41653366\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Expression correlation only; no functional manipulation of SBK2 in this disease context\",\n        \"Causal contribution of SBK2 loss to DRC not tested\",\n        \"No substrate or pathway implicated in this model\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SBK2 kinase activity is regulated upstream and how its sarcomeric, mitochondrial, and inflammasome functions are coordinated remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No upstream activator or signaling input identified\",\n        \"No structural model of the kinase\",\n        \"Unclear whether sarcomere maintenance is direct or downstream of metabolic effects\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NDUFV1\", \"HSPA1A\", \"TOM70\", \"NLRP3\", \"Tollip\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}