{"gene":"SGTA","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":1999,"finding":"Yeast Sgt1p physically associates with Skp1p in vivo and in vitro, and is required for assembling the kinetochore complex CBF3 via activation of Ctf13p; Sgt1p also associates with SCF (Skp1p/Cdc53p/F-box protein) ubiquitin ligase, and human SGT1 rescues a yeast sgt1 null mutation, indicating evolutionary conservation of function.","method":"Dosage suppressor screen, in vivo and in vitro binding assays, genetic complementation, in vitro ubiquitination assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (in vitro binding, in vivo co-association, functional complementation, ubiquitination assay) in a foundational paper","pmids":["10445024"],"is_preprint":false},{"year":2003,"finding":"Human Sgt1 binds HSP90 through the CS (CHORD-SGT1) domain, not the TPR domain; NMR spectroscopy showed that only the CS domain physically interacts with HSP90, and that Sgt1 can bind HSP90 in the absence of ATP (unlike p23).","method":"NMR spectroscopy, in vitro binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — NMR structure-based interaction mapping with mutational validation","pmids":["14761955"],"is_preprint":false},{"year":2003,"finding":"Human Sgt1 interacts with S100A6 (calcyclin) and other S100 proteins (S100B, S100P) in a calcium-regulated manner via its C-terminal 71 residues; S100A6 does not affect Skp1-Sgt1 binding, indicating separate interaction domains; S100A6 inhibits CK2-mediated phosphorylation of Sgt1; co-immunoprecipitation confirmed the interaction in HEp-2 cells.","method":"Affinity chromatography, chemical cross-linking, co-immunoprecipitation, in vitro kinase assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple methods (pulldown, crosslink, co-IP, kinase assay) from single lab","pmids":["12746458"],"is_preprint":false},{"year":2007,"finding":"Many mammalian NLR proteins (NALP3, IPAF, Nod2) interact with SGT1 and HSP90; knockdown of SGT1 by siRNA abrogated inflammasome activity (NALP3, IPAF); HSP90 inhibition blocked Nod2-mediated NF-κB activation and NALP3-mediated inflammation in mice, demonstrating SGT1-HSP90 as essential for mammalian NLR inflammasome function.","method":"Co-immunoprecipitation, siRNA knockdown, mouse inflammation model, chemical inhibition of HSP90","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — Strong: reciprocal Co-IP, siRNA with defined cellular phenotype, in vivo rescue, replicated across multiple NLRs","pmids":["17435760"],"is_preprint":false},{"year":2006,"finding":"SARS-CoV 7a protein interacts with human SGTA (hSGT); the interaction was identified by yeast two-hybrid and confirmed by co-immunoprecipitation and co-localization in cells; TPR2 domain (aa 125-158) of SGTA is essential for this interaction.","method":"Yeast two-hybrid, co-immunoprecipitation, cellular co-localization, deletion mutagenesis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, multiple methods but limited functional follow-up","pmids":["16580632"],"is_preprint":false},{"year":2009,"finding":"CK2 phosphorylates Ser361 of Sgt1, and this phosphorylation negatively regulates Sgt1 dimerization, which is important for kinetochore assembly.","method":"In vitro kinase assay, mutational analysis, dimerization assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro kinase assay with mutagenesis, single lab","pmids":["19398558"],"is_preprint":false},{"year":2009,"finding":"Drosophila Sgt1 is required for centrosome maturation; sgt1 mutant neuroblasts show decreased Polo kinase protein levels, and overexpression of Polo substantially rescues the centrosome and spindle defects, placing Sgt1 upstream of Polo stabilization.","method":"Drosophila genetics, mutant phenotype analysis, protein level quantification, epistasis by rescue with Polo overexpression","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with defined phenotypic rescue, strong mechanistic conclusion","pmids":["19131964"],"is_preprint":false},{"year":2010,"finding":"Human Hsp90-Sgt1 interacts with the Mis12 complex at kinetochores; inhibition of Hsp90 or Sgt1 destabilizes the Mis12 complex and delays chromosome alignment by impairing microtubule-binding site formation; Skp1 co-inhibition partially rescues Mis12 at kinetochores, defining Hsp90-Sgt1 as a chaperone for Mis12 complex assembly.","method":"Co-immunoprecipitation, RNAi/chemical inhibition, live-cell imaging, kinetochore protein quantification","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, clear epistasis with rescue experiment","pmids":["20404110"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of the Hsp90-CS-CHORD ternary complex was determined; structural and biochemical analyses show that both CHORD (from Rar1) and CS (from Sgt1) domains can independently bind Hsp90 and coexist in complexes with Hsp90; mutational analyses define the architecture of this ternary complex that recruits NLR receptors.","method":"X-ray crystallography, mutagenesis, biochemical binding assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutational and biochemical validation","pmids":["20670895"],"is_preprint":false},{"year":2012,"finding":"Plk1 phosphorylates Sgt1 at Ser331 at kinetochores during prometaphase; this phosphorylation enhances association of Hsp90-Sgt1 with the MIS12 complex, stabilizes MIS12 at kinetochores, and promotes NDC80 complex recruitment for microtubule attachment; disruption of this phosphorylation causes chromosome misalignment.","method":"In vitro kinase assay, phospho-specific antibody, co-immunoprecipitation, mutagenesis, kinetochore protein quantification, live imaging","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro kinase assay with mutagenesis, multiple orthogonal readouts, clear mechanistic pathway","pmids":["22869522"],"is_preprint":false},{"year":2012,"finding":"SGTA antagonizes BAG6-mediated ubiquitination of mislocalized proteins; SGTA actively promotes deubiquitination of already ubiquitinated mislocalized proteins, reversing BAG6 function and inhibiting substrate-specific degradation; this effect is independent of SGTA's TPR motifs and thus does not require Hsp70/Hsp90 chaperones.","method":"Cell-based ubiquitination assay, steady-state protein level analysis, SGTA overexpression/domain mutants","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — mechanistic dissection with domain mutants, functional rescue experiments, clear pathway placement","pmids":["23129660"],"is_preprint":false},{"year":2013,"finding":"BAG6 binds SGTA via its N-terminal UBL domain; UBL4A (a second BAG6 complex subunit) also binds SGTA through its UBL, competing with BAG6 for SGTA interaction, such that SGTA can bind either BAG6 or UBL4A but not both simultaneously; the central region of BAG6 (not the UBL or BAG domains) binds tail-anchored substrates.","method":"In vitro binding assays, deletion mutagenesis, heterologous subcellular localization assay in yeast","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — multiple in vitro binding approaches with mutagenesis, single lab","pmids":["23533635"],"is_preprint":false},{"year":2014,"finding":"SGTA associates with and specifically regulates the androgen, glucocorticoid, and progesterone receptors (but not mineralocorticoid or estrogen receptors); SGTA knockdown enhances receptor activity while overexpression suppresses it; SGTA binds Hsp70 and Hsp90 directly in vitro but predominantly co-precipitates with Hsp70 from cell lysates, placing SGTA at an early Hsp70-mediated step in the chaperone cycle; SGTA overexpression completely abolishes FKBP52-mediated receptor regulation.","method":"Yeast reporter assay, mammalian reporter assay, siRNA knockdown, in vitro binding assay, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal assays (yeast, mammalian, in vitro), clear specificity defined across receptor family, functional epistasis with FKBP52","pmids":["24753260"],"is_preprint":false},{"year":2015,"finding":"The C-terminal region of Rpn13 (a 26S proteasome ubiquitin receptor) binds directly to the TPR domain of SGTA; SGTA overexpression increases steady-state levels of mislocalized membrane proteins in a manner dependent on this Rpn13 interaction; overexpression of the SGTA-binding region of Rpn13 or TPR domain point mutations both inhibit SGTA-proteasome binding and reduce substrate protection, indicating SGTA regulates proteasomal access of mislocalized proteins.","method":"Co-immunoprecipitation, point mutagenesis, steady-state protein level assay, competition experiments","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with mutagenesis and functional readout, single lab","pmids":["26169395"],"is_preprint":false},{"year":2012,"finding":"Drosophila Sgt1 acts via an LKB1/AMPK pathway to establish cortical polarity in larval neuroblasts; sgt1 mutants phenocopy hsp83 (Hsp90), LKB1, and AMPKα mutants in prophase apical polarity defects; activated AMPKα rescues the sgt1 mutant polarity phenotype, placing Sgt1/Hsp90 upstream of LKB1-AMPK in this pathway.","method":"Drosophila genetic screen, epistasis analysis, phenotypic rescue with activated AMPKα","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with multiple alleles and pathway rescue, single organism","pmids":["22248825"],"is_preprint":false},{"year":2013,"finding":"Salmonella effector SspH2 interacts with SGT1 specifically via its NLR co-chaperone function (not its cell cycle function); SGT1 enhances SspH2 in vitro ubiquitination activity and protein stability; SspH2 ubiquitinates Nod1 and can activate Nod1 in an agonist-independent manner when catalytically active, requiring SGT1 interaction.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, domain-selective interaction mapping, cell-based NF-κB reporter assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution of ubiquitination, Co-IP, functional assays with defined mutants, cross-kingdom validation","pmids":["23935490"],"is_preprint":false},{"year":2020,"finding":"SGTA is recruited to ribosomes synthesizing diverse membrane proteins before the transmembrane domain emerges from the ribosome; for co-translational ER delivery clients, SGTA reduces co-translational ubiquitination of complex membrane proteins with multiple hydrophobic signal sequences, complementing the role of SRP.","method":"Ribosome association assay, ubiquitination assay, selective depletion of SGTA, live-cell experiments","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 — direct ribosome recruitment assay with functional ubiquitination readout, single lab","pmids":["32216016"],"is_preprint":false},{"year":2020,"finding":"MAPK phosphorylation of SGT1 at a canonical MAPK target motif in its C-terminal domain contributes to NLR-mediated immune activation; a bacterial effector RipAC inhibits the interaction between SGT1 and MAP kinases, preventing this phosphorylation and suppressing NLR (RPS2)-mediated immunity; this phosphorylation is enhanced upon immune signaling activation and contributes to resistance against R. solanacearum.","method":"Co-immunoprecipitation, in vitro/in vivo phosphorylation assays, mutagenesis, plant resistance assays","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical and genetic approaches, single lab","pmids":["32976518"],"is_preprint":false},{"year":2008,"finding":"Sgt1 has co-chaperone properties: it attenuates citrate synthase aggregation at elevated temperature (anti-aggregation activity comparable to p23); HSF-1 transcription factor binds the heat shock element in the Sgt1 promoter; Sgt1 protein levels are upregulated upon heat shock or HSP90 inhibitor (radicicol) treatment in human cells.","method":"Citrate synthase aggregation assay, luciferase reporter assay, EMSA, Western blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1-3 — in vitro chaperone assay plus promoter analysis, single lab","pmids":["18358234"],"is_preprint":false},{"year":2020,"finding":"Necdin interacts with SGT1 (identified by yeast two-hybrid), and necdin enables the SGT1-HSP90 chaperone machinery to stabilize BMAL1; depletion of necdin or SGT1/HSP90 leads to BMAL1 degradation via the ubiquitin-proteasome system, altering circadian clock gene expression and rhythms.","method":"Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, mouse behavioral assay, protein stability assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple methods (Y2H, Co-IP, KD) with in vivo phenotype, single lab","pmids":["32667666"],"is_preprint":false}],"current_model":"Human SGTA (Small Glutamine-rich Tetratricopeptide repeat-containing protein Alpha) is an Hsp90/Hsp70 co-chaperone that uses its CS domain to bind HSP90 and its TPR domain to interact with Hsp70, Rpn13 (proteasome), and client proteins; it functions in (1) quality control of mislocalized/tail-anchored membrane proteins by antagonizing BAG6-mediated ubiquitination and promoting deubiquitination, (2) chaperoning of NLR innate immune receptors and steroid hormone receptors (androgen, glucocorticoid, progesterone) in concert with HSP90, (3) kinetochore assembly by stabilizing the MIS12 complex in a Plk1-phosphorylation-dependent manner, and (4) protection of nascent transmembrane domain-containing proteins from co-translational ubiquitination at the ribosome."},"narrative":{"teleology":[{"year":1999,"claim":"The foundational discovery that Sgt1 physically associates with Skp1 and is required for kinetochore complex CBF3 assembly and SCF ubiquitin ligase function established SGT1 as a dual-function scaffold bridging cell-cycle and kinetochore pathways, with human SGT1 rescuing yeast null mutants to confirm conservation.","evidence":"Dosage suppressor screen, in vivo/in vitro binding, genetic complementation in yeast","pmids":["10445024"],"confidence":"High","gaps":["No direct structural basis for Skp1–Sgt1 interaction defined","Mechanism of Ctf13 activation unclear","Mammalian kinetochore function not yet tested"]},{"year":2003,"claim":"NMR spectroscopy resolved that the CS domain — not the TPR domain — mediates the direct HSP90 interaction, establishing the domain architecture that underlies all subsequent co-chaperone models for SGT1.","evidence":"NMR spectroscopy and in vitro binding with domain truncations","pmids":["14761955"],"confidence":"High","gaps":["Full-length Sgt1–HSP90 complex structure not yet determined","Functional consequence of CS–HSP90 interaction for clients unknown at this point"]},{"year":2007,"claim":"SGT1–HSP90 was shown to be essential for mammalian NLR inflammasome function, with SGT1 knockdown abrogating NALP3 and IPAF activity and HSP90 inhibition blocking Nod2-mediated NF-κB signaling in vivo, establishing the innate immune co-chaperone role.","evidence":"Co-immunoprecipitation across multiple NLRs, siRNA, HSP90 chemical inhibition, mouse inflammation model","pmids":["17435760"],"confidence":"High","gaps":["Mechanism by which SGT1 stabilizes NLR clients not structurally resolved","Whether SGT1 functions catalytically or as a scaffold for NLRs not distinguished"]},{"year":2008,"claim":"Demonstration that SGT1 possesses intrinsic co-chaperone activity — suppressing citrate synthase aggregation comparably to p23 — and that its expression is transcriptionally upregulated by HSF-1 upon heat shock, placing SGT1 within the heat-shock response network.","evidence":"In vitro aggregation assay, EMSA, luciferase reporter, Western blot in human cells","pmids":["18358234"],"confidence":"Medium","gaps":["Anti-aggregation activity not linked to a specific client in vivo","Relative contribution versus other co-chaperones not assessed"]},{"year":2009,"claim":"Drosophila genetics revealed that Sgt1 is required for centrosome maturation by stabilizing Polo kinase protein levels, while CK2 phosphorylation of Sgt1 at Ser361 was shown to regulate its dimerization — two regulatory inputs governing its mitotic functions.","evidence":"Drosophila mutant phenotype with Polo rescue; in vitro kinase assay with mutational analysis of dimerization","pmids":["19131964","19398558"],"confidence":"High","gaps":["Whether CK2-regulated dimerization is relevant in mammalian cells not tested","Direct physical interaction between Sgt1 and Polo not shown"]},{"year":2010,"claim":"Two key advances established the structural and functional basis for SGT1's kinetochore and immune roles: the crystal structure of the HSP90–CS–CHORD ternary complex defined the architecture for NLR recruitment, while functional studies showed HSP90–SGT1 directly chaperones the MIS12 complex at kinetochores for microtubule-binding site formation.","evidence":"X-ray crystallography with mutagenesis; RNAi/chemical inhibition with live-cell imaging and kinetochore protein quantification","pmids":["20670895","20404110"],"confidence":"High","gaps":["How SGT1 discriminates between kinetochore and NLR clients not resolved","Structural basis for Mis12 complex recognition unknown"]},{"year":2012,"claim":"The quality-control axis of SGT1 was defined: SGT1 antagonizes BAG6-mediated ubiquitination of mislocalized proteins and actively promotes deubiquitination independently of its TPR domain (and thus HSP70/HSP90), while Plk1 phosphorylation of SGT1 at Ser331 was shown to enhance MIS12 stabilization at kinetochores during prometaphase.","evidence":"Cell-based ubiquitination assays with domain mutants; in vitro kinase assay, phospho-specific antibody, co-IP, live imaging","pmids":["23129660","22869522"],"confidence":"High","gaps":["Identity of the deubiquitinase recruited by SGTA unknown","Whether Plk1 phosphorylation also influences NLR chaperoning not tested"]},{"year":2013,"claim":"The molecular logic of the SGTA–BAG6 quality-control complex was refined: BAG6's UBL domain and UBL4A compete for SGTA binding, creating a switching mechanism, while the Salmonella effector SspH2 was shown to co-opt SGT1's NLR co-chaperone function to activate Nod1 ubiquitination.","evidence":"In vitro binding/mutagenesis for BAG6 complex; Co-IP, in vitro ubiquitination, NF-κB reporter for SspH2–SGT1","pmids":["23533635","23935490"],"confidence":"High","gaps":["Stoichiometry of the SGTA–BAG6–UBL4A complex in vivo undetermined","Whether SspH2 exploitation of SGT1 is unique among bacterial effectors unknown"]},{"year":2014,"claim":"SGT1 was placed as a negative regulator of androgen, glucocorticoid, and progesterone receptors — but not estrogen or mineralocorticoid receptors — acting at an early HSP70-dependent step of the chaperone cycle and antagonizing FKBP52-mediated receptor potentiation.","evidence":"Yeast and mammalian reporter assays, siRNA, in vitro binding, co-immunoprecipitation","pmids":["24753260"],"confidence":"High","gaps":["Structural basis for receptor selectivity unknown","Whether SGTA competes with FKBP52 for the same binding site not resolved"]},{"year":2015,"claim":"The proteasome connection was established: Rpn13's C-terminal region directly binds the SGTA TPR domain, and this interaction is required for SGTA to shield mislocalized membrane proteins from proteasomal degradation.","evidence":"Co-immunoprecipitation, point mutagenesis, competition and steady-state protein level assays","pmids":["26169395"],"confidence":"Medium","gaps":["Whether SGTA delivers substrates to or retrieves them from the proteasome not distinguished","In vivo confirmation with endogenous Rpn13 mutant lacking the SGTA-binding region not performed"]},{"year":2020,"claim":"Three studies expanded SGT1's scope: SGTA is recruited to ribosomes before transmembrane domain emergence to suppress co-translational ubiquitination; MAPK phosphorylation of SGT1 potentiates NLR immunity and is targeted by bacterial effector RipAC; and necdin recruits the SGT1–HSP90 machinery to stabilize the circadian clock protein BMAL1.","evidence":"Ribosome association/ubiquitination assays; in vivo/in vitro phosphorylation with plant resistance assays; Y2H, Co-IP, siRNA, mouse behavioral analysis","pmids":["32216016","32976518","32667666"],"confidence":"Medium","gaps":["How SGTA recognizes ribosome-nascent chain complexes before TMD exposure is mechanistically undefined","Whether MAPK phosphorylation of SGT1 operates in mammalian NLR signaling not tested","Whether necdin-mediated BMAL1 stabilization is the primary circadian role of SGT1 or one of several is unknown"]},{"year":null,"claim":"Key unresolved questions include how SGTA discriminates among its diverse client classes (NLRs, steroid receptors, mislocalized proteins, kinetochore complexes, BMAL1), the identity of the deubiquitinase recruited by SGTA to reverse BAG6-mediated ubiquitination, and whether the ribosome-associated and post-translational quality-control functions represent a unified surveillance pathway.","evidence":"","pmids":[],"confidence":"Low","gaps":["No client-discrimination mechanism defined","Deubiquitinase identity unknown","Unified model integrating co-translational and post-translational QC roles not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[1,3,7,8,12,18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,12,13]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[7,9]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,7,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10,11,12]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[16]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,8,15,17]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,5,6,7,9]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[10,11,13,16]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[19]}],"complexes":["BAG6 quality-control complex","HSP90-SGT1-RAR1/CHORD ternary complex"],"partners":["HSP90AA1","HSPA1A","BAG6","UBL4A","SKP1","ADRM1","NDN"],"other_free_text":[]},"mechanistic_narrative":"SGT1 (SUGT1) is a multifunctional co-chaperone that partners with HSP90 via its CS domain and with HSP70/proteasomal Rpn13 via its TPR domain to regulate protein quality control, kinetochore assembly, and innate immune signaling. In the quality-control pathway, SGT1 antagonizes BAG6-mediated ubiquitination of mislocalized membrane proteins and promotes their deubiquitination, while also protecting nascent transmembrane-domain-containing proteins from co-translational ubiquitination at the ribosome [PMID:23129660, PMID:32216016, PMID:26169395]. SGT1 functions as an essential co-chaperone for NLR inflammasome receptors (NALP3, IPAF, Nod1/Nod2), where the ternary HSP90–CS–CHORD complex recruits and stabilizes NLR clients, and MAPK-mediated phosphorylation of SGT1 further potentiates NLR-dependent immune activation [PMID:17435760, PMID:20670895, PMID:32976518]. At kinetochores, Plk1-dependent phosphorylation of SGT1 at Ser331 enhances HSP90–SGT1 association with the MIS12 complex, promoting NDC80 recruitment and accurate chromosome alignment, while SGT1 also regulates steroid hormone receptor activity at an early HSP70-dependent step of the chaperone cycle [PMID:22869522, PMID:24753260]."},"prefetch_data":{"uniprot":{"accession":"O43765","full_name":"Small glutamine-rich tetratricopeptide repeat-containing protein alpha","aliases":["Alpha-SGT","Vpu-binding protein","UBP"],"length_aa":313,"mass_kda":34.1,"function":"Co-chaperone that binds misfolded and hydrophobic patches-containing client proteins in the cytosol. Mediates their targeting to the endoplasmic reticulum but also regulates their sorting to the proteasome when targeting fails (PubMed:28104892). Functions in tail-anchored/type II transmembrane proteins membrane insertion constituting with ASNA1 and the BAG6 complex a targeting module (PubMed:28104892). Functions upstream of the BAG6 complex and ASNA1, binding more rapidly the transmembrane domain of newly synthesized proteins (PubMed:25535373, PubMed:28104892). It is also involved in the regulation of the endoplasmic reticulum-associated misfolded protein catabolic process via its interaction with BAG6: collaborates with the BAG6 complex to maintain hydrophobic substrates in non-ubiquitinated states (PubMed:23129660, PubMed:25179605). Competes with RNF126 for interaction with BAG6, preventing the ubiquitination of client proteins associated with the BAG6 complex (PubMed:27193484). Binds directly to HSC70 and HSP70 and regulates their ATPase activity (PubMed:18759457) (Microbial infection) In case of infection by polyomavirus, involved in the virus endoplasmic reticulum membrane penetration and infection via interaction with DNAJB12, DNAJB14 and HSPA8/Hsc70 (PubMed:24675744)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/O43765/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SGTA","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":[{"gene":"ARPC3","stoichiometry":0.2},{"gene":"BTF3","stoichiometry":0.2},{"gene":"GDI2","stoichiometry":0.2},{"gene":"HSPA8","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SGTA","total_profiled":1310},"omim":[{"mim_id":"620526","title":"SMALL GLUTAMINE-RICH TETRATRICOPEPTIDE REPEAT COCHAPERONE, BETA; SGTB","url":"https://www.omim.org/entry/620526"},{"mim_id":"613945","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 5, BETA; DNAJC5B","url":"https://www.omim.org/entry/613945"},{"mim_id":"612056","title":"GUIDED ENTRY OF TAIL-ANCHORED PROTEINS FACTOR 4; GET4","url":"https://www.omim.org/entry/612056"},{"mim_id":"611203","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 5; DNAJC5","url":"https://www.omim.org/entry/611203"},{"mim_id":"603419","title":"SMALL GLUTAMINE-RICH TETRATRICOPEPTIDE REPEAT-CONTAINING COCHAPERONE, ALPHA; SGTA","url":"https://www.omim.org/entry/603419"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SGTA"},"hgnc":{"alias_symbol":["UBP","SGT1","Vpu","hSGT","alphaSGT"],"prev_symbol":["SGT"]},"alphafold":{"accession":"O43765","domains":[{"cath_id":"1.20.5.420","chopping":"1-70","consensus_level":"medium","plddt":87.3337,"start":1,"end":70},{"cath_id":"1.25.40.10","chopping":"85-207","consensus_level":"medium","plddt":97.1181,"start":85,"end":207}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43765","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43765-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43765-F1-predicted_aligned_error_v6.png","plddt_mean":81.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SGTA","jax_strain_url":"https://www.jax.org/strain/search?query=SGTA"},"sequence":{"accession":"O43765","fasta_url":"https://rest.uniprot.org/uniprotkb/O43765.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43765/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43765"}},"corpus_meta":[{"pmid":"18200009","id":"PMC_18200009","title":"Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu.","date":"2008","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/18200009","citation_count":1507,"is_preprint":false},{"pmid":"12507430","id":"PMC_12507430","title":"Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde.","date":"2002","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/12507430","citation_count":556,"is_preprint":false},{"pmid":"1433512","id":"PMC_1433512","title":"Human immunodeficiency virus type 1 Vpu protein induces rapid degradation of CD4.","date":"1992","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/1433512","citation_count":490,"is_preprint":false},{"pmid":"11847307","id":"PMC_11847307","title":"The RAR1 interactor SGT1, an essential component of R gene-triggered disease resistance.","date":"2002","source":"Science (New York, 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establish cortical polarity in larval neuroblasts.","date":"2012","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/22248825","citation_count":20,"is_preprint":false},{"pmid":"24019872","id":"PMC_24019872","title":"The Hv-SGT1 gene from Haynaldia villosa contributes to resistances towards both biotrophic and hemi-biotrophic pathogens in common wheat (Triticum aestivum L.).","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24019872","citation_count":20,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44175,"output_tokens":4805,"usd":0.1023},"stage2":{"model":"claude-opus-4-6","input_tokens":8311,"output_tokens":3344,"usd":0.187732},"total_usd":0.290032,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"Yeast Sgt1p physically associates with Skp1p in vivo and in vitro, and is required for assembling the kinetochore complex CBF3 via activation of Ctf13p; Sgt1p also associates with SCF (Skp1p/Cdc53p/F-box protein) ubiquitin ligase, and human SGT1 rescues a yeast sgt1 null mutation, indicating evolutionary conservation of function.\",\n      \"method\": \"Dosage suppressor screen, in vivo and in vitro binding assays, genetic complementation, in vitro ubiquitination assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (in vitro binding, in vivo co-association, functional complementation, ubiquitination assay) in a foundational paper\",\n      \"pmids\": [\"10445024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human Sgt1 binds HSP90 through the CS (CHORD-SGT1) domain, not the TPR domain; NMR spectroscopy showed that only the CS domain physically interacts with HSP90, and that Sgt1 can bind HSP90 in the absence of ATP (unlike p23).\",\n      \"method\": \"NMR spectroscopy, in vitro binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure-based interaction mapping with mutational validation\",\n      \"pmids\": [\"14761955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human Sgt1 interacts with S100A6 (calcyclin) and other S100 proteins (S100B, S100P) in a calcium-regulated manner via its C-terminal 71 residues; S100A6 does not affect Skp1-Sgt1 binding, indicating separate interaction domains; S100A6 inhibits CK2-mediated phosphorylation of Sgt1; co-immunoprecipitation confirmed the interaction in HEp-2 cells.\",\n      \"method\": \"Affinity chromatography, chemical cross-linking, co-immunoprecipitation, in vitro kinase assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple methods (pulldown, crosslink, co-IP, kinase assay) from single lab\",\n      \"pmids\": [\"12746458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Many mammalian NLR proteins (NALP3, IPAF, Nod2) interact with SGT1 and HSP90; knockdown of SGT1 by siRNA abrogated inflammasome activity (NALP3, IPAF); HSP90 inhibition blocked Nod2-mediated NF-κB activation and NALP3-mediated inflammation in mice, demonstrating SGT1-HSP90 as essential for mammalian NLR inflammasome function.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, mouse inflammation model, chemical inhibition of HSP90\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Strong: reciprocal Co-IP, siRNA with defined cellular phenotype, in vivo rescue, replicated across multiple NLRs\",\n      \"pmids\": [\"17435760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SARS-CoV 7a protein interacts with human SGTA (hSGT); the interaction was identified by yeast two-hybrid and confirmed by co-immunoprecipitation and co-localization in cells; TPR2 domain (aa 125-158) of SGTA is essential for this interaction.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, cellular co-localization, deletion mutagenesis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, multiple methods but limited functional follow-up\",\n      \"pmids\": [\"16580632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CK2 phosphorylates Ser361 of Sgt1, and this phosphorylation negatively regulates Sgt1 dimerization, which is important for kinetochore assembly.\",\n      \"method\": \"In vitro kinase assay, mutational analysis, dimerization assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase assay with mutagenesis, single lab\",\n      \"pmids\": [\"19398558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Drosophila Sgt1 is required for centrosome maturation; sgt1 mutant neuroblasts show decreased Polo kinase protein levels, and overexpression of Polo substantially rescues the centrosome and spindle defects, placing Sgt1 upstream of Polo stabilization.\",\n      \"method\": \"Drosophila genetics, mutant phenotype analysis, protein level quantification, epistasis by rescue with Polo overexpression\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with defined phenotypic rescue, strong mechanistic conclusion\",\n      \"pmids\": [\"19131964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human Hsp90-Sgt1 interacts with the Mis12 complex at kinetochores; inhibition of Hsp90 or Sgt1 destabilizes the Mis12 complex and delays chromosome alignment by impairing microtubule-binding site formation; Skp1 co-inhibition partially rescues Mis12 at kinetochores, defining Hsp90-Sgt1 as a chaperone for Mis12 complex assembly.\",\n      \"method\": \"Co-immunoprecipitation, RNAi/chemical inhibition, live-cell imaging, kinetochore protein quantification\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, clear epistasis with rescue experiment\",\n      \"pmids\": [\"20404110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of the Hsp90-CS-CHORD ternary complex was determined; structural and biochemical analyses show that both CHORD (from Rar1) and CS (from Sgt1) domains can independently bind Hsp90 and coexist in complexes with Hsp90; mutational analyses define the architecture of this ternary complex that recruits NLR receptors.\",\n      \"method\": \"X-ray crystallography, mutagenesis, biochemical binding assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutational and biochemical validation\",\n      \"pmids\": [\"20670895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Plk1 phosphorylates Sgt1 at Ser331 at kinetochores during prometaphase; this phosphorylation enhances association of Hsp90-Sgt1 with the MIS12 complex, stabilizes MIS12 at kinetochores, and promotes NDC80 complex recruitment for microtubule attachment; disruption of this phosphorylation causes chromosome misalignment.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibody, co-immunoprecipitation, mutagenesis, kinetochore protein quantification, live imaging\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase assay with mutagenesis, multiple orthogonal readouts, clear mechanistic pathway\",\n      \"pmids\": [\"22869522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SGTA antagonizes BAG6-mediated ubiquitination of mislocalized proteins; SGTA actively promotes deubiquitination of already ubiquitinated mislocalized proteins, reversing BAG6 function and inhibiting substrate-specific degradation; this effect is independent of SGTA's TPR motifs and thus does not require Hsp70/Hsp90 chaperones.\",\n      \"method\": \"Cell-based ubiquitination assay, steady-state protein level analysis, SGTA overexpression/domain mutants\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection with domain mutants, functional rescue experiments, clear pathway placement\",\n      \"pmids\": [\"23129660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BAG6 binds SGTA via its N-terminal UBL domain; UBL4A (a second BAG6 complex subunit) also binds SGTA through its UBL, competing with BAG6 for SGTA interaction, such that SGTA can bind either BAG6 or UBL4A but not both simultaneously; the central region of BAG6 (not the UBL or BAG domains) binds tail-anchored substrates.\",\n      \"method\": \"In vitro binding assays, deletion mutagenesis, heterologous subcellular localization assay in yeast\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro binding approaches with mutagenesis, single lab\",\n      \"pmids\": [\"23533635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SGTA associates with and specifically regulates the androgen, glucocorticoid, and progesterone receptors (but not mineralocorticoid or estrogen receptors); SGTA knockdown enhances receptor activity while overexpression suppresses it; SGTA binds Hsp70 and Hsp90 directly in vitro but predominantly co-precipitates with Hsp70 from cell lysates, placing SGTA at an early Hsp70-mediated step in the chaperone cycle; SGTA overexpression completely abolishes FKBP52-mediated receptor regulation.\",\n      \"method\": \"Yeast reporter assay, mammalian reporter assay, siRNA knockdown, in vitro binding assay, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal assays (yeast, mammalian, in vitro), clear specificity defined across receptor family, functional epistasis with FKBP52\",\n      \"pmids\": [\"24753260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The C-terminal region of Rpn13 (a 26S proteasome ubiquitin receptor) binds directly to the TPR domain of SGTA; SGTA overexpression increases steady-state levels of mislocalized membrane proteins in a manner dependent on this Rpn13 interaction; overexpression of the SGTA-binding region of Rpn13 or TPR domain point mutations both inhibit SGTA-proteasome binding and reduce substrate protection, indicating SGTA regulates proteasomal access of mislocalized proteins.\",\n      \"method\": \"Co-immunoprecipitation, point mutagenesis, steady-state protein level assay, competition experiments\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with mutagenesis and functional readout, single lab\",\n      \"pmids\": [\"26169395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Drosophila Sgt1 acts via an LKB1/AMPK pathway to establish cortical polarity in larval neuroblasts; sgt1 mutants phenocopy hsp83 (Hsp90), LKB1, and AMPKα mutants in prophase apical polarity defects; activated AMPKα rescues the sgt1 mutant polarity phenotype, placing Sgt1/Hsp90 upstream of LKB1-AMPK in this pathway.\",\n      \"method\": \"Drosophila genetic screen, epistasis analysis, phenotypic rescue with activated AMPKα\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple alleles and pathway rescue, single organism\",\n      \"pmids\": [\"22248825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Salmonella effector SspH2 interacts with SGT1 specifically via its NLR co-chaperone function (not its cell cycle function); SGT1 enhances SspH2 in vitro ubiquitination activity and protein stability; SspH2 ubiquitinates Nod1 and can activate Nod1 in an agonist-independent manner when catalytically active, requiring SGT1 interaction.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, domain-selective interaction mapping, cell-based NF-κB reporter assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution of ubiquitination, Co-IP, functional assays with defined mutants, cross-kingdom validation\",\n      \"pmids\": [\"23935490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SGTA is recruited to ribosomes synthesizing diverse membrane proteins before the transmembrane domain emerges from the ribosome; for co-translational ER delivery clients, SGTA reduces co-translational ubiquitination of complex membrane proteins with multiple hydrophobic signal sequences, complementing the role of SRP.\",\n      \"method\": \"Ribosome association assay, ubiquitination assay, selective depletion of SGTA, live-cell experiments\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct ribosome recruitment assay with functional ubiquitination readout, single lab\",\n      \"pmids\": [\"32216016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MAPK phosphorylation of SGT1 at a canonical MAPK target motif in its C-terminal domain contributes to NLR-mediated immune activation; a bacterial effector RipAC inhibits the interaction between SGT1 and MAP kinases, preventing this phosphorylation and suppressing NLR (RPS2)-mediated immunity; this phosphorylation is enhanced upon immune signaling activation and contributes to resistance against R. solanacearum.\",\n      \"method\": \"Co-immunoprecipitation, in vitro/in vivo phosphorylation assays, mutagenesis, plant resistance assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical and genetic approaches, single lab\",\n      \"pmids\": [\"32976518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Sgt1 has co-chaperone properties: it attenuates citrate synthase aggregation at elevated temperature (anti-aggregation activity comparable to p23); HSF-1 transcription factor binds the heat shock element in the Sgt1 promoter; Sgt1 protein levels are upregulated upon heat shock or HSP90 inhibitor (radicicol) treatment in human cells.\",\n      \"method\": \"Citrate synthase aggregation assay, luciferase reporter assay, EMSA, Western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-3 — in vitro chaperone assay plus promoter analysis, single lab\",\n      \"pmids\": [\"18358234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Necdin interacts with SGT1 (identified by yeast two-hybrid), and necdin enables the SGT1-HSP90 chaperone machinery to stabilize BMAL1; depletion of necdin or SGT1/HSP90 leads to BMAL1 degradation via the ubiquitin-proteasome system, altering circadian clock gene expression and rhythms.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, mouse behavioral assay, protein stability assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple methods (Y2H, Co-IP, KD) with in vivo phenotype, single lab\",\n      \"pmids\": [\"32667666\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human SGTA (Small Glutamine-rich Tetratricopeptide repeat-containing protein Alpha) is an Hsp90/Hsp70 co-chaperone that uses its CS domain to bind HSP90 and its TPR domain to interact with Hsp70, Rpn13 (proteasome), and client proteins; it functions in (1) quality control of mislocalized/tail-anchored membrane proteins by antagonizing BAG6-mediated ubiquitination and promoting deubiquitination, (2) chaperoning of NLR innate immune receptors and steroid hormone receptors (androgen, glucocorticoid, progesterone) in concert with HSP90, (3) kinetochore assembly by stabilizing the MIS12 complex in a Plk1-phosphorylation-dependent manner, and (4) protection of nascent transmembrane domain-containing proteins from co-translational ubiquitination at the ribosome.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SGT1 (SUGT1) is a multifunctional co-chaperone that partners with HSP90 via its CS domain and with HSP70/proteasomal Rpn13 via its TPR domain to regulate protein quality control, kinetochore assembly, and innate immune signaling. In the quality-control pathway, SGT1 antagonizes BAG6-mediated ubiquitination of mislocalized membrane proteins and promotes their deubiquitination, while also protecting nascent transmembrane-domain-containing proteins from co-translational ubiquitination at the ribosome [PMID:23129660, PMID:32216016, PMID:26169395]. SGT1 functions as an essential co-chaperone for NLR inflammasome receptors (NALP3, IPAF, Nod1/Nod2), where the ternary HSP90–CS–CHORD complex recruits and stabilizes NLR clients, and MAPK-mediated phosphorylation of SGT1 further potentiates NLR-dependent immune activation [PMID:17435760, PMID:20670895, PMID:32976518]. At kinetochores, Plk1-dependent phosphorylation of SGT1 at Ser331 enhances HSP90–SGT1 association with the MIS12 complex, promoting NDC80 recruitment and accurate chromosome alignment, while SGT1 also regulates steroid hormone receptor activity at an early HSP70-dependent step of the chaperone cycle [PMID:22869522, PMID:24753260].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"The foundational discovery that Sgt1 physically associates with Skp1 and is required for kinetochore complex CBF3 assembly and SCF ubiquitin ligase function established SGT1 as a dual-function scaffold bridging cell-cycle and kinetochore pathways, with human SGT1 rescuing yeast null mutants to confirm conservation.\",\n      \"evidence\": \"Dosage suppressor screen, in vivo/in vitro binding, genetic complementation in yeast\",\n      \"pmids\": [\"10445024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No direct structural basis for Skp1–Sgt1 interaction defined\", \"Mechanism of Ctf13 activation unclear\", \"Mammalian kinetochore function not yet tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"NMR spectroscopy resolved that the CS domain — not the TPR domain — mediates the direct HSP90 interaction, establishing the domain architecture that underlies all subsequent co-chaperone models for SGT1.\",\n      \"evidence\": \"NMR spectroscopy and in vitro binding with domain truncations\",\n      \"pmids\": [\"14761955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length Sgt1–HSP90 complex structure not yet determined\", \"Functional consequence of CS–HSP90 interaction for clients unknown at this point\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"SGT1–HSP90 was shown to be essential for mammalian NLR inflammasome function, with SGT1 knockdown abrogating NALP3 and IPAF activity and HSP90 inhibition blocking Nod2-mediated NF-κB signaling in vivo, establishing the innate immune co-chaperone role.\",\n      \"evidence\": \"Co-immunoprecipitation across multiple NLRs, siRNA, HSP90 chemical inhibition, mouse inflammation model\",\n      \"pmids\": [\"17435760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which SGT1 stabilizes NLR clients not structurally resolved\", \"Whether SGT1 functions catalytically or as a scaffold for NLRs not distinguished\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstration that SGT1 possesses intrinsic co-chaperone activity — suppressing citrate synthase aggregation comparably to p23 — and that its expression is transcriptionally upregulated by HSF-1 upon heat shock, placing SGT1 within the heat-shock response network.\",\n      \"evidence\": \"In vitro aggregation assay, EMSA, luciferase reporter, Western blot in human cells\",\n      \"pmids\": [\"18358234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Anti-aggregation activity not linked to a specific client in vivo\", \"Relative contribution versus other co-chaperones not assessed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Drosophila genetics revealed that Sgt1 is required for centrosome maturation by stabilizing Polo kinase protein levels, while CK2 phosphorylation of Sgt1 at Ser361 was shown to regulate its dimerization — two regulatory inputs governing its mitotic functions.\",\n      \"evidence\": \"Drosophila mutant phenotype with Polo rescue; in vitro kinase assay with mutational analysis of dimerization\",\n      \"pmids\": [\"19131964\", \"19398558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CK2-regulated dimerization is relevant in mammalian cells not tested\", \"Direct physical interaction between Sgt1 and Polo not shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Two key advances established the structural and functional basis for SGT1's kinetochore and immune roles: the crystal structure of the HSP90–CS–CHORD ternary complex defined the architecture for NLR recruitment, while functional studies showed HSP90–SGT1 directly chaperones the MIS12 complex at kinetochores for microtubule-binding site formation.\",\n      \"evidence\": \"X-ray crystallography with mutagenesis; RNAi/chemical inhibition with live-cell imaging and kinetochore protein quantification\",\n      \"pmids\": [\"20670895\", \"20404110\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SGT1 discriminates between kinetochore and NLR clients not resolved\", \"Structural basis for Mis12 complex recognition unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The quality-control axis of SGT1 was defined: SGT1 antagonizes BAG6-mediated ubiquitination of mislocalized proteins and actively promotes deubiquitination independently of its TPR domain (and thus HSP70/HSP90), while Plk1 phosphorylation of SGT1 at Ser331 was shown to enhance MIS12 stabilization at kinetochores during prometaphase.\",\n      \"evidence\": \"Cell-based ubiquitination assays with domain mutants; in vitro kinase assay, phospho-specific antibody, co-IP, live imaging\",\n      \"pmids\": [\"23129660\", \"22869522\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the deubiquitinase recruited by SGTA unknown\", \"Whether Plk1 phosphorylation also influences NLR chaperoning not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The molecular logic of the SGTA–BAG6 quality-control complex was refined: BAG6's UBL domain and UBL4A compete for SGTA binding, creating a switching mechanism, while the Salmonella effector SspH2 was shown to co-opt SGT1's NLR co-chaperone function to activate Nod1 ubiquitination.\",\n      \"evidence\": \"In vitro binding/mutagenesis for BAG6 complex; Co-IP, in vitro ubiquitination, NF-κB reporter for SspH2–SGT1\",\n      \"pmids\": [\"23533635\", \"23935490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the SGTA–BAG6–UBL4A complex in vivo undetermined\", \"Whether SspH2 exploitation of SGT1 is unique among bacterial effectors unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"SGT1 was placed as a negative regulator of androgen, glucocorticoid, and progesterone receptors — but not estrogen or mineralocorticoid receptors — acting at an early HSP70-dependent step of the chaperone cycle and antagonizing FKBP52-mediated receptor potentiation.\",\n      \"evidence\": \"Yeast and mammalian reporter assays, siRNA, in vitro binding, co-immunoprecipitation\",\n      \"pmids\": [\"24753260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for receptor selectivity unknown\", \"Whether SGTA competes with FKBP52 for the same binding site not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The proteasome connection was established: Rpn13's C-terminal region directly binds the SGTA TPR domain, and this interaction is required for SGTA to shield mislocalized membrane proteins from proteasomal degradation.\",\n      \"evidence\": \"Co-immunoprecipitation, point mutagenesis, competition and steady-state protein level assays\",\n      \"pmids\": [\"26169395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SGTA delivers substrates to or retrieves them from the proteasome not distinguished\", \"In vivo confirmation with endogenous Rpn13 mutant lacking the SGTA-binding region not performed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Three studies expanded SGT1's scope: SGTA is recruited to ribosomes before transmembrane domain emergence to suppress co-translational ubiquitination; MAPK phosphorylation of SGT1 potentiates NLR immunity and is targeted by bacterial effector RipAC; and necdin recruits the SGT1–HSP90 machinery to stabilize the circadian clock protein BMAL1.\",\n      \"evidence\": \"Ribosome association/ubiquitination assays; in vivo/in vitro phosphorylation with plant resistance assays; Y2H, Co-IP, siRNA, mouse behavioral analysis\",\n      \"pmids\": [\"32216016\", \"32976518\", \"32667666\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How SGTA recognizes ribosome-nascent chain complexes before TMD exposure is mechanistically undefined\", \"Whether MAPK phosphorylation of SGT1 operates in mammalian NLR signaling not tested\", \"Whether necdin-mediated BMAL1 stabilization is the primary circadian role of SGT1 or one of several is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how SGTA discriminates among its diverse client classes (NLRs, steroid receptors, mislocalized proteins, kinetochore complexes, BMAL1), the identity of the deubiquitinase recruited by SGTA to reverse BAG6-mediated ubiquitination, and whether the ribosome-associated and post-translational quality-control functions represent a unified surveillance pathway.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No client-discrimination mechanism defined\", \"Deubiquitinase identity unknown\", \"Unified model integrating co-translational and post-translational QC roles not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [1, 3, 7, 8, 12, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 12, 13]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [7, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 7, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10, 11, 12]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 8, 15, 17]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 5, 6, 7, 9]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [10, 11, 13, 16]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"complexes\": [\n      \"BAG6 quality-control complex\",\n      \"HSP90-SGT1-RAR1/CHORD ternary complex\"\n    ],\n    \"partners\": [\n      \"HSP90AA1\",\n      \"HSPA1A\",\n      \"BAG6\",\n      \"UBL4A\",\n      \"SKP1\",\n      \"ADRM1\",\n      \"NDN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}