{"gene":"SUGT1","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2020,"finding":"SUGT1 stabilizes microtubule plus-ends (+MTs) in host cells by modulating microtubule acetylation and promoting formation of EB1 comets, thereby facilitating HIV-1 retrograde trafficking and nuclear import of the viral genome; SUGT1 depletion impairs HIV-1 replication.","method":"siRNA knockdown, immunofluorescence imaging of EB1 comets, microtubule acetylation assays, HIV-1 infection permissiveness assays in lymphocytes and macrophages","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype (EB1 comets, microtubule acetylation, viral trafficking), multiple orthogonal methods in single lab","pmids":["32514048"],"is_preprint":false},{"year":2020,"finding":"SUGT1 is required for kinetochore assembly in mitotic myoblasts; loss of SUGT1 causes mislocalization of kinetochore components Dsn1 and Hec1, impairing kinetochore assembly and myoblast proliferation.","method":"Loss-of-function (SAM lncRNA deletion and direct Sugt1 knockdown), immunofluorescence of kinetochore markers (Dsn1, Hec1) in mitotic cells, muscle regeneration assays in vivo","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO/KD with specific kinetochore localization phenotype, multiple orthogonal methods, single lab","pmids":["32483152"],"is_preprint":false},{"year":2023,"finding":"SUGT1 interacts with the cytosolic E3 ubiquitin ligase TRIM21 in myoblasts and promotes ubiquitination of p21 via TRIM21; loss of Sugt1 causes p21 accumulation leading to G2/M cell cycle arrest and cellular senescence.","method":"Co-immunoprecipitation (SUGT1–TRIM21 interaction), ubiquitination assays for p21, siRNA/inducible knockout in muscle stem cells, cell cycle analysis","journal":"Life medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus ubiquitination functional assay, single lab, two orthogonal methods","pmids":["39872547"],"is_preprint":false},{"year":2022,"finding":"Co-expression of SUGT1 as a chaperone dramatically enhances yield and quality of recombinant leucine-rich repeat (LRR) proteins including SHOC2 and the SHOC2-MRAS-PPP1CA (SMP) complex in baculovirus-infected insect cells, demonstrating SUGT1's chaperone function for LRR-containing proteins.","method":"Polycistronic baculovirus expression, protein yield/quality assessment of LRR proteins with and without SUGT1 co-expression","journal":"Protein expression and purification","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct biochemical reconstitution in vitro (baculovirus system), single lab, functional chaperone activity demonstrated","pmids":["35131438"],"is_preprint":false},{"year":2023,"finding":"SUGT1 is a direct target of miR-141-3p; SUGT1 overexpression reverses the inhibitory effect of miR-141-3p on pyroptosis in colonic epithelial cells, placing SUGT1 upstream of NLRP3/caspase-1/GSDMD pyroptosis pathway.","method":"Dual luciferase reporter assay (miR-141-3p targeting SUGT1 3'UTR), SUGT1 overexpression rescue experiment, pyroptosis marker quantification (western blot, ELISA, flow cytometry)","journal":"Autoimmunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual luciferase confirmation plus functional rescue experiment with defined pyroptosis markers, single lab","pmids":["37317573"],"is_preprint":false},{"year":2026,"finding":"SUGT1 stabilizes the NLRP3/HSP90 complex, keeping NLRP3 in an inactive (resting) state; the drug Notoginsenoside-Fa binds SUGT1 directly and stabilizes this SUGT1/HSP90/NLRP3 complex to suppress NLRP3 inflammasome activation.","method":"Immunoprecipitation (SUGT1-HSP90-NLRP3 complex), CETSA, SPR, molecular docking, Dot blot for Noto-Fa/SUGT1 interaction, western blot of inflammasome proteins","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus biophysical binding assays (SPR, CETSA), single lab, multiple orthogonal methods","pmids":["42036143"],"is_preprint":false},{"year":2025,"finding":"SUGT1 promotes FH (fumarate hydratase) protein degradation via the ubiquitin-proteasome pathway in ovarian cancer cells; FH knockdown partially reverses the antiproliferative and anti-migratory effects of SUGT1 knockdown, and SUGT1 acts upstream of phosphorylated PI3K/AKT signaling.","method":"siRNA knockdown, ubiquitin-proteasome pathway analysis, rescue experiments (FH KD in SUGT1 KD background), western blot for p-PI3K/AKT and Vimentin","journal":"Journal of ovarian research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method set (KD + rescue), no direct ubiquitination reconstitution reported in abstract","pmids":["40731365"],"is_preprint":false},{"year":2024,"finding":"The transcription factor ELF1 directly binds to the SUGT1 promoter and enhances its transcription, as demonstrated by promoter analysis and chromatin immunoprecipitation in ovarian cancer cells.","method":"Promoter analysis, chromatin immunoprecipitation (ChIP)","journal":"Translational oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP in single lab with no functional mutagenesis of binding site reported","pmids":["39167956"],"is_preprint":false},{"year":2026,"finding":"The C. parvum effector CpCML binds SUGT1 directly and induces its redistribution from cytoplasm to nucleus, reprogramming host PI3K/AKT-NF-κB signaling and impairing autophagic flux; SUGT1 depletion promotes NF-κB activation and autophagy marker accumulation (LC3-II, p62), while SUGT1 overexpression restores autophagic flux and reduces parasite burden.","method":"Biochemical binding assays, co-immunoprecipitation (CpCML–SUGT1), subcellular fractionation/immunofluorescence, siRNA knockdown, overexpression, PI3K inhibitor epistasis","journal":"Microbial pathogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays plus genetic epistasis (siRNA KD, OE, PI3K inhibitor), single lab, multiple orthogonal methods","pmids":["42119958"],"is_preprint":false},{"year":2025,"finding":"HSP90 and its co-chaperone SUGT1 mediate tau phosphorylation via GSK-3β in an Aβ42-dependent manner in a cell model; HSP90/SUGT1 also increase intracellular Aβ42 concentration, placing SUGT1 at the intersection of Aβ and tau proteostasis networks.","method":"Cell model overexpression/knockdown, western blot for tau phosphorylation, Aβ42 quantification","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single cell model, single lab, no mutagenesis or reconstitution","pmids":["bio_10.1101_2025.03.28.646065"],"is_preprint":true}],"current_model":"SUGT1 is a molecular chaperone—functioning as an HSP90 co-chaperone—that (1) is required for kinetochore assembly during mitosis by ensuring correct localization of Dsn1 and Hec1; (2) stabilizes microtubule plus-ends via EB1 comet formation and microtubule acetylation modulation; (3) promotes ubiquitin-mediated degradation of substrates (p21 via TRIM21; FH via the proteasome); (4) maintains NLRP3 inflammasome in an inactive state through the SUGT1/HSP90/NLRP3 complex; and (5) serves as a chaperone for leucine-rich repeat proteins including components of the SHOC2-MRAS-PPP1CA MAP kinase holoenzyme."},"narrative":{"mechanistic_narrative":"SUGT1 is a molecular chaperone that supports protein quality control and stability across multiple cellular processes, frequently acting in concert with HSP90 [PMID:42036143]. In mitosis it is required for kinetochore assembly, ensuring correct localization of the kinetochore components Dsn1 and Hec1, and its loss impairs proliferation [PMID:32483152]. SUGT1 also stabilizes microtubule plus-ends by modulating microtubule acetylation and promoting EB1 comet formation, a function exploited by HIV-1 for retrograde trafficking and nuclear import [PMID:32514048]. A recurring theme is its chaperone activity toward leucine-rich repeat proteins: co-expression of SUGT1 markedly enhances the yield and quality of SHOC2 and the SHOC2-MRAS-PPP1CA holoenzyme [PMID:35131438]. SUGT1 additionally engages the ubiquitin-proteasome system, interacting with the E3 ligase TRIM21 to promote p21 ubiquitination and thereby preventing G2/M arrest and senescence [PMID:39872547]. Through a SUGT1/HSP90/NLRP3 complex it holds the NLRP3 inflammasome in an inactive resting state [PMID:42036143], and it lies upstream of the NLRP3/caspase-1/GSDMD pyroptosis axis [PMID:37317573]. SUGT1 is also a target of pathogen effectors that hijack its function, as the C. parvum effector CpCML binds SUGT1 and drives its nuclear redistribution to reprogram PI3K/AKT-NF-κB signaling and impair autophagy [PMID:42119958].","teleology":[{"year":2020,"claim":"Establishing that SUGT1 controls microtubule plus-end dynamics defined a cytoskeletal function and revealed how a chaperone-associated factor can be co-opted for viral trafficking.","evidence":"siRNA knockdown with EB1 comet imaging, microtubule acetylation assays and HIV-1 permissiveness in lymphocytes and macrophages","pmids":["32514048"],"confidence":"Medium","gaps":["Direct biochemical mechanism linking SUGT1 to EB1 or tubulin acetylation enzymes not defined","Whether the +MT role requires HSP90 not tested"]},{"year":2020,"claim":"Demonstrating that SUGT1 is needed for correct loading of Dsn1 and Hec1 placed it as a required factor in kinetochore assembly during mitosis.","evidence":"Loss-of-function knockout/knockdown with immunofluorescence of kinetochore markers and in vivo muscle regeneration assays","pmids":["32483152"],"confidence":"Medium","gaps":["Whether SUGT1 chaperones kinetochore subunits directly versus indirectly is unresolved","Molecular interaction with Dsn1/Hec1 not shown biochemically"]},{"year":2022,"claim":"Reconstituting LRR protein expression with SUGT1 co-expression provided direct biochemical evidence for its chaperone activity toward leucine-rich repeat proteins.","evidence":"Polycistronic baculovirus expression of SHOC2 and the SHOC2-MRAS-PPP1CA complex with and without SUGT1, assessing yield and quality","pmids":["35131438"],"confidence":"Medium","gaps":["Whether SUGT1 binds LRR clients directly in vivo not shown","Requirement for HSP90 in this chaperone activity not tested"]},{"year":2023,"claim":"Identifying the SUGT1-TRIM21 interaction and p21 ubiquitination connected SUGT1 to ubiquitin-mediated proteostasis and cell-cycle/senescence control.","evidence":"Reciprocal co-immunoprecipitation, p21 ubiquitination assays and cell cycle analysis in muscle stem cells","pmids":["39872547"],"confidence":"Medium","gaps":["Whether SUGT1 acts as a chaperone/adaptor for TRIM21 or modulates ligase activity is unclear","Direct SUGT1-p21 contact not demonstrated"]},{"year":2023,"claim":"Placing SUGT1 downstream of miR-141-3p and upstream of NLRP3/caspase-1/GSDMD linked it to pyroptosis regulation.","evidence":"Dual luciferase 3'UTR reporter, SUGT1 overexpression rescue and pyroptosis marker quantification in colonic epithelial cells","pmids":["37317573"],"confidence":"Medium","gaps":["Mechanism by which SUGT1 modulates NLRP3 in this context not resolved","Direct molecular interaction not established here"]},{"year":2024,"claim":"Showing ELF1 binds the SUGT1 promoter began to define transcriptional control of SUGT1 expression.","evidence":"Promoter analysis and chromatin immunoprecipitation in ovarian cancer cells","pmids":["39167956"],"confidence":"Low","gaps":["No functional mutagenesis of the ELF1 binding site reported","Physiological contexts of ELF1-driven SUGT1 expression unknown"]},{"year":2025,"claim":"Linking SUGT1 to FH degradation and PI3K/AKT signaling extended its proteasome-directed role to cancer cell proliferation and migration.","evidence":"siRNA knockdown, ubiquitin-proteasome pathway analysis and FH knockdown rescue in ovarian cancer cells","pmids":["40731365"],"confidence":"Low","gaps":["No direct ubiquitination reconstitution reported","Whether SUGT1 directly binds FH unknown","Single method set in one lab"]},{"year":2025,"claim":"A cell-model study positioned the HSP90/SUGT1 chaperone module within the Aβ/tau proteostasis network via GSK-3β.","evidence":"Cell model overexpression/knockdown with western blot for tau phosphorylation and Aβ42 quantification (preprint)","pmids":["bio_10.1101_2025.03.28.646065"],"confidence":"Low","gaps":["Preprint, single cell model, no mutagenesis or reconstitution","Direct client relationship not demonstrated"]},{"year":2026,"claim":"Defining the SUGT1/HSP90/NLRP3 complex established a direct chaperone-based mechanism keeping the NLRP3 inflammasome inactive and identified SUGT1 as a druggable node.","evidence":"Immunoprecipitation of the SUGT1-HSP90-NLRP3 complex plus CETSA, SPR and dot blot for Notoginsenoside-Fa binding","pmids":["42036143"],"confidence":"Medium","gaps":["Structural basis of NLRP3 stabilization not resolved","How activation releases NLRP3 from the complex not defined"]},{"year":2026,"claim":"Discovering that the C. parvum effector CpCML binds SUGT1 and forces its nuclear relocation revealed pathogen hijacking of SUGT1 to reprogram PI3K/AKT-NF-κB signaling and autophagy.","evidence":"Biochemical binding assays, co-IP, subcellular fractionation, knockdown/overexpression and PI3K inhibitor epistasis","pmids":["42119958"],"confidence":"Medium","gaps":["Endogenous nucleocytoplasmic shuttling determinants of SUGT1 not mapped","Whether nuclear SUGT1 retains chaperone function unknown"]},{"year":null,"claim":"How SUGT1's HSP90 co-chaperone activity is mechanistically partitioned across its diverse client repertoire—kinetochore subunits, microtubule regulators, LRR proteins, NLRP3, and ubiquitination substrates—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of SUGT1-client engagement","Determinants of client selectivity unknown","Distinction between direct chaperone and adaptor roles not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[3,5]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[8]}],"complexes":["SUGT1/HSP90/NLRP3 complex","kinetochore"],"partners":["HSP90","NLRP3","TRIM21","SHOC2","MRAS","PPP1CA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y2Z0","full_name":"Protein SGT1 homolog","aliases":["Protein 40-6-3","Sgt1","Suppressor of G2 allele of SKP1 homolog"],"length_aa":365,"mass_kda":41.0,"function":"May play a role in ubiquitination and subsequent proteasomal degradation of target proteins","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9Y2Z0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SUGT1","classification":"Common Essential","n_dependent_lines":816,"n_total_lines":1208,"dependency_fraction":0.6754966887417219},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"FKBP5","stoichiometry":4.0},{"gene":"FKBP8","stoichiometry":4.0},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"DNAJB6","stoichiometry":0.2},{"gene":"DNAJC7","stoichiometry":0.2},{"gene":"IPO5","stoichiometry":0.2},{"gene":"PLA2G4A","stoichiometry":0.2},{"gene":"PTGES3","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SUGT1","total_profiled":1310},"omim":[{"mim_id":"604098","title":"SGT1 HOMOLOG, MIS12 KINETOCHORE COMPLEX ASSEMBLY COCHAPERONE; SUGT1","url":"https://www.omim.org/entry/604098"},{"mim_id":"263450","title":"POLYDACTYLY, POSTAXIAL, TYPE A5; PAPA5","url":"https://www.omim.org/entry/263450"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear bodies","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Acrosome","reliability":"Additional"},{"location":"Flagellar centriole","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SUGT1"},"hgnc":{"alias_symbol":["SGT1"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y2Z0","domains":[{"cath_id":"1.25.40.10","chopping":"19-119_143-158","consensus_level":"high","plddt":87.5117,"start":19,"end":158},{"cath_id":"2.60.40.790","chopping":"173-246","consensus_level":"high","plddt":87.3722,"start":173,"end":246},{"cath_id":"-","chopping":"303-365","consensus_level":"medium","plddt":79.6451,"start":303,"end":365}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2Z0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2Z0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2Z0-F1-predicted_aligned_error_v6.png","plddt_mean":76.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SUGT1","jax_strain_url":"https://www.jax.org/strain/search?query=SUGT1"},"sequence":{"accession":"Q9Y2Z0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y2Z0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y2Z0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2Z0"}},"corpus_meta":[{"pmid":"32483152","id":"PMC_32483152","title":"Long noncoding RNA SAM promotes myoblast proliferation through stabilizing Sugt1 and facilitating kinetochore assembly.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32483152","citation_count":29,"is_preprint":false},{"pmid":"37317573","id":"PMC_37317573","title":"miR-141-3p alleviates ulcerative colitis by targeting SUGT1 to inhibit colonic epithelial cell pyroptosis.","date":"2023","source":"Autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/37317573","citation_count":16,"is_preprint":false},{"pmid":"35131438","id":"PMC_35131438","title":"Polycistronic baculovirus expression of SUGT1 enables high-yield production of recombinant leucine-rich repeat proteins and protein complexes.","date":"2022","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/35131438","citation_count":15,"is_preprint":false},{"pmid":"32514048","id":"PMC_32514048","title":"SUGT1 controls susceptibility to HIV-1 infection by stabilizing microtubule plus-ends.","date":"2020","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/32514048","citation_count":13,"is_preprint":false},{"pmid":"20126976","id":"PMC_20126976","title":"Overexpression of SUGT1 in human colorectal cancer and its clinicopathological significance.","date":"2010","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/20126976","citation_count":9,"is_preprint":false},{"pmid":"39872547","id":"PMC_39872547","title":"Sugt1 loss in skeletal muscle stem cells impairs muscle regeneration and causes premature muscle aging.","date":"2023","source":"Life medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39872547","citation_count":7,"is_preprint":false},{"pmid":"39167956","id":"PMC_39167956","title":"SUGT1 regulates the progression of ovarian cancer through the AKT/PI3K/mTOR signaling pathway.","date":"2024","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39167956","citation_count":2,"is_preprint":false},{"pmid":"40731365","id":"PMC_40731365","title":"Mechanism by which SUGT1 downregulates FH to promote proliferation and migration in serous ovarian cancer.","date":"2025","source":"Journal of ovarian research","url":"https://pubmed.ncbi.nlm.nih.gov/40731365","citation_count":0,"is_preprint":false},{"pmid":"42036143","id":"PMC_42036143","title":"Notoginsenoside-Fa mitigates vascular endothelial permeability via targeting SUGT1 to stabilize NLRP3 in a resting state.","date":"2026","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/42036143","citation_count":0,"is_preprint":false},{"pmid":"42119958","id":"PMC_42119958","title":"CpCML subverts host PI3K/AKT-NF-κB signaling and autophagic flux via direct interaction with SUGT1 to facilitate Cryptosporidium parvum infection.","date":"2026","source":"Microbial pathogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/42119958","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.28.646065","title":"Linking Aβ and tau in the amyloid cascade through the intersection of their proteostasis networks","date":"2025-04-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.28.646065","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7397,"output_tokens":2609,"usd":0.030663,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9761,"output_tokens":3589,"usd":0.069265,"stage2_stop_reason":"end_turn"},"total_usd":0.099928,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"SUGT1 stabilizes microtubule plus-ends (+MTs) in host cells by modulating microtubule acetylation and promoting formation of EB1 comets, thereby facilitating HIV-1 retrograde trafficking and nuclear import of the viral genome; SUGT1 depletion impairs HIV-1 replication.\",\n      \"method\": \"siRNA knockdown, immunofluorescence imaging of EB1 comets, microtubule acetylation assays, HIV-1 infection permissiveness assays in lymphocytes and macrophages\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype (EB1 comets, microtubule acetylation, viral trafficking), multiple orthogonal methods in single lab\",\n      \"pmids\": [\"32514048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SUGT1 is required for kinetochore assembly in mitotic myoblasts; loss of SUGT1 causes mislocalization of kinetochore components Dsn1 and Hec1, impairing kinetochore assembly and myoblast proliferation.\",\n      \"method\": \"Loss-of-function (SAM lncRNA deletion and direct Sugt1 knockdown), immunofluorescence of kinetochore markers (Dsn1, Hec1) in mitotic cells, muscle regeneration assays in vivo\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO/KD with specific kinetochore localization phenotype, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"32483152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SUGT1 interacts with the cytosolic E3 ubiquitin ligase TRIM21 in myoblasts and promotes ubiquitination of p21 via TRIM21; loss of Sugt1 causes p21 accumulation leading to G2/M cell cycle arrest and cellular senescence.\",\n      \"method\": \"Co-immunoprecipitation (SUGT1–TRIM21 interaction), ubiquitination assays for p21, siRNA/inducible knockout in muscle stem cells, cell cycle analysis\",\n      \"journal\": \"Life medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus ubiquitination functional assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"39872547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Co-expression of SUGT1 as a chaperone dramatically enhances yield and quality of recombinant leucine-rich repeat (LRR) proteins including SHOC2 and the SHOC2-MRAS-PPP1CA (SMP) complex in baculovirus-infected insect cells, demonstrating SUGT1's chaperone function for LRR-containing proteins.\",\n      \"method\": \"Polycistronic baculovirus expression, protein yield/quality assessment of LRR proteins with and without SUGT1 co-expression\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct biochemical reconstitution in vitro (baculovirus system), single lab, functional chaperone activity demonstrated\",\n      \"pmids\": [\"35131438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SUGT1 is a direct target of miR-141-3p; SUGT1 overexpression reverses the inhibitory effect of miR-141-3p on pyroptosis in colonic epithelial cells, placing SUGT1 upstream of NLRP3/caspase-1/GSDMD pyroptosis pathway.\",\n      \"method\": \"Dual luciferase reporter assay (miR-141-3p targeting SUGT1 3'UTR), SUGT1 overexpression rescue experiment, pyroptosis marker quantification (western blot, ELISA, flow cytometry)\",\n      \"journal\": \"Autoimmunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual luciferase confirmation plus functional rescue experiment with defined pyroptosis markers, single lab\",\n      \"pmids\": [\"37317573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SUGT1 stabilizes the NLRP3/HSP90 complex, keeping NLRP3 in an inactive (resting) state; the drug Notoginsenoside-Fa binds SUGT1 directly and stabilizes this SUGT1/HSP90/NLRP3 complex to suppress NLRP3 inflammasome activation.\",\n      \"method\": \"Immunoprecipitation (SUGT1-HSP90-NLRP3 complex), CETSA, SPR, molecular docking, Dot blot for Noto-Fa/SUGT1 interaction, western blot of inflammasome proteins\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus biophysical binding assays (SPR, CETSA), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"42036143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SUGT1 promotes FH (fumarate hydratase) protein degradation via the ubiquitin-proteasome pathway in ovarian cancer cells; FH knockdown partially reverses the antiproliferative and anti-migratory effects of SUGT1 knockdown, and SUGT1 acts upstream of phosphorylated PI3K/AKT signaling.\",\n      \"method\": \"siRNA knockdown, ubiquitin-proteasome pathway analysis, rescue experiments (FH KD in SUGT1 KD background), western blot for p-PI3K/AKT and Vimentin\",\n      \"journal\": \"Journal of ovarian research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method set (KD + rescue), no direct ubiquitination reconstitution reported in abstract\",\n      \"pmids\": [\"40731365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The transcription factor ELF1 directly binds to the SUGT1 promoter and enhances its transcription, as demonstrated by promoter analysis and chromatin immunoprecipitation in ovarian cancer cells.\",\n      \"method\": \"Promoter analysis, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP in single lab with no functional mutagenesis of binding site reported\",\n      \"pmids\": [\"39167956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The C. parvum effector CpCML binds SUGT1 directly and induces its redistribution from cytoplasm to nucleus, reprogramming host PI3K/AKT-NF-κB signaling and impairing autophagic flux; SUGT1 depletion promotes NF-κB activation and autophagy marker accumulation (LC3-II, p62), while SUGT1 overexpression restores autophagic flux and reduces parasite burden.\",\n      \"method\": \"Biochemical binding assays, co-immunoprecipitation (CpCML–SUGT1), subcellular fractionation/immunofluorescence, siRNA knockdown, overexpression, PI3K inhibitor epistasis\",\n      \"journal\": \"Microbial pathogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays plus genetic epistasis (siRNA KD, OE, PI3K inhibitor), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"42119958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HSP90 and its co-chaperone SUGT1 mediate tau phosphorylation via GSK-3β in an Aβ42-dependent manner in a cell model; HSP90/SUGT1 also increase intracellular Aβ42 concentration, placing SUGT1 at the intersection of Aβ and tau proteostasis networks.\",\n      \"method\": \"Cell model overexpression/knockdown, western blot for tau phosphorylation, Aβ42 quantification\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single cell model, single lab, no mutagenesis or reconstitution\",\n      \"pmids\": [\"bio_10.1101_2025.03.28.646065\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SUGT1 is a molecular chaperone—functioning as an HSP90 co-chaperone—that (1) is required for kinetochore assembly during mitosis by ensuring correct localization of Dsn1 and Hec1; (2) stabilizes microtubule plus-ends via EB1 comet formation and microtubule acetylation modulation; (3) promotes ubiquitin-mediated degradation of substrates (p21 via TRIM21; FH via the proteasome); (4) maintains NLRP3 inflammasome in an inactive state through the SUGT1/HSP90/NLRP3 complex; and (5) serves as a chaperone for leucine-rich repeat proteins including components of the SHOC2-MRAS-PPP1CA MAP kinase holoenzyme.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SUGT1 is a molecular chaperone that supports protein quality control and stability across multiple cellular processes, frequently acting in concert with HSP90 [#5]. In mitosis it is required for kinetochore assembly, ensuring correct localization of the kinetochore components Dsn1 and Hec1, and its loss impairs proliferation [#1]. SUGT1 also stabilizes microtubule plus-ends by modulating microtubule acetylation and promoting EB1 comet formation, a function exploited by HIV-1 for retrograde trafficking and nuclear import [#0]. A recurring theme is its chaperone activity toward leucine-rich repeat proteins: co-expression of SUGT1 markedly enhances the yield and quality of SHOC2 and the SHOC2-MRAS-PPP1CA holoenzyme [#3]. SUGT1 additionally engages the ubiquitin-proteasome system, interacting with the E3 ligase TRIM21 to promote p21 ubiquitination and thereby preventing G2/M arrest and senescence [#2]. Through a SUGT1/HSP90/NLRP3 complex it holds the NLRP3 inflammasome in an inactive resting state [#5], and it lies upstream of the NLRP3/caspase-1/GSDMD pyroptosis axis [#4]. SUGT1 is also a target of pathogen effectors that hijack its function, as the C. parvum effector CpCML binds SUGT1 and drives its nuclear redistribution to reprogram PI3K/AKT-NF-\\u03baB signaling and impair autophagy [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing that SUGT1 controls microtubule plus-end dynamics defined a cytoskeletal function and revealed how a chaperone-associated factor can be co-opted for viral trafficking.\",\n      \"evidence\": \"siRNA knockdown with EB1 comet imaging, microtubule acetylation assays and HIV-1 permissiveness in lymphocytes and macrophages\",\n      \"pmids\": [\"32514048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical mechanism linking SUGT1 to EB1 or tubulin acetylation enzymes not defined\", \"Whether the +MT role requires HSP90 not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating that SUGT1 is needed for correct loading of Dsn1 and Hec1 placed it as a required factor in kinetochore assembly during mitosis.\",\n      \"evidence\": \"Loss-of-function knockout/knockdown with immunofluorescence of kinetochore markers and in vivo muscle regeneration assays\",\n      \"pmids\": [\"32483152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SUGT1 chaperones kinetochore subunits directly versus indirectly is unresolved\", \"Molecular interaction with Dsn1/Hec1 not shown biochemically\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reconstituting LRR protein expression with SUGT1 co-expression provided direct biochemical evidence for its chaperone activity toward leucine-rich repeat proteins.\",\n      \"evidence\": \"Polycistronic baculovirus expression of SHOC2 and the SHOC2-MRAS-PPP1CA complex with and without SUGT1, assessing yield and quality\",\n      \"pmids\": [\"35131438\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SUGT1 binds LRR clients directly in vivo not shown\", \"Requirement for HSP90 in this chaperone activity not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying the SUGT1-TRIM21 interaction and p21 ubiquitination connected SUGT1 to ubiquitin-mediated proteostasis and cell-cycle/senescence control.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, p21 ubiquitination assays and cell cycle analysis in muscle stem cells\",\n      \"pmids\": [\"39872547\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SUGT1 acts as a chaperone/adaptor for TRIM21 or modulates ligase activity is unclear\", \"Direct SUGT1-p21 contact not demonstrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placing SUGT1 downstream of miR-141-3p and upstream of NLRP3/caspase-1/GSDMD linked it to pyroptosis regulation.\",\n      \"evidence\": \"Dual luciferase 3'UTR reporter, SUGT1 overexpression rescue and pyroptosis marker quantification in colonic epithelial cells\",\n      \"pmids\": [\"37317573\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SUGT1 modulates NLRP3 in this context not resolved\", \"Direct molecular interaction not established here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing ELF1 binds the SUGT1 promoter began to define transcriptional control of SUGT1 expression.\",\n      \"evidence\": \"Promoter analysis and chromatin immunoprecipitation in ovarian cancer cells\",\n      \"pmids\": [\"39167956\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional mutagenesis of the ELF1 binding site reported\", \"Physiological contexts of ELF1-driven SUGT1 expression unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linking SUGT1 to FH degradation and PI3K/AKT signaling extended its proteasome-directed role to cancer cell proliferation and migration.\",\n      \"evidence\": \"siRNA knockdown, ubiquitin-proteasome pathway analysis and FH knockdown rescue in ovarian cancer cells\",\n      \"pmids\": [\"40731365\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct ubiquitination reconstitution reported\", \"Whether SUGT1 directly binds FH unknown\", \"Single method set in one lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A cell-model study positioned the HSP90/SUGT1 chaperone module within the A\\u03b2/tau proteostasis network via GSK-3\\u03b2.\",\n      \"evidence\": \"Cell model overexpression/knockdown with western blot for tau phosphorylation and A\\u03b242 quantification (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.03.28.646065\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, single cell model, no mutagenesis or reconstitution\", \"Direct client relationship not demonstrated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defining the SUGT1/HSP90/NLRP3 complex established a direct chaperone-based mechanism keeping the NLRP3 inflammasome inactive and identified SUGT1 as a druggable node.\",\n      \"evidence\": \"Immunoprecipitation of the SUGT1-HSP90-NLRP3 complex plus CETSA, SPR and dot blot for Notoginsenoside-Fa binding\",\n      \"pmids\": [\"42036143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of NLRP3 stabilization not resolved\", \"How activation releases NLRP3 from the complex not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Discovering that the C. parvum effector CpCML binds SUGT1 and forces its nuclear relocation revealed pathogen hijacking of SUGT1 to reprogram PI3K/AKT-NF-\\u03baB signaling and autophagy.\",\n      \"evidence\": \"Biochemical binding assays, co-IP, subcellular fractionation, knockdown/overexpression and PI3K inhibitor epistasis\",\n      \"pmids\": [\"42119958\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous nucleocytoplasmic shuttling determinants of SUGT1 not mapped\", \"Whether nuclear SUGT1 retains chaperone function unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SUGT1's HSP90 co-chaperone activity is mechanistically partitioned across its diverse client repertoire\\u2014kinetochore subunits, microtubule regulators, LRR proteins, NLRP3, and ubiquitination substrates\\u2014remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of SUGT1-client engagement\", \"Determinants of client selectivity unknown\", \"Distinction between direct chaperone and adaptor roles not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\n      \"SUGT1/HSP90/NLRP3 complex\",\n      \"kinetochore\"\n    ],\n    \"partners\": [\n      \"HSP90\",\n      \"NLRP3\",\n      \"TRIM21\",\n      \"SHOC2\",\n      \"MRAS\",\n      \"PPP1CA\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}