{"gene":"SAP18","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":1997,"finding":"SAP18 is a component of the mammalian Sin3 (mSin3) complex that also contains HDAC1, HDAC2, and SAP30. SAP18 directly interacts with mSin3, and when tethered to a promoter, SAP18 represses transcription in vivo.","method":"Co-immunoprecipitation, cDNA cloning, in vivo transcription reporter assay, direct interaction demonstrated biochemically","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, in vivo reporter assay, direct interaction confirmed; foundational paper replicated by multiple subsequent studies","pmids":["9150135"],"is_preprint":false},{"year":2002,"finding":"Mouse Suppressor of Fused [mSu(fu)] specifically interacts with SAP18 and functionally cooperates with SAP18 to repress Gli-mediated transcription by recruiting the SAP18-mSin3 complex to promoters containing Gli-binding elements.","method":"Co-immunoprecipitation, in vivo transcription reporter assay, promoter recruitment assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus functional reporter assay, single lab with two orthogonal methods","pmids":["11960000"],"is_preprint":false},{"year":2004,"finding":"mSufu interacts with SAP18 (confirmed by independent biochemical assays beyond yeast two-hybrid), and co-expression of SAP18 (normally nuclear) causes translocation of predominantly cytoplasmic mSufu to the nucleus.","method":"Yeast two-hybrid, independent biochemical co-immunoprecipitation, cell transfection/localization assay","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction confirmed by independent biochemical assay; localization consequence shown by co-expression, single lab","pmids":["14611647"],"is_preprint":false},{"year":2000,"finding":"Drosophila SAP18 (dSAP18) interacts with the GAGA factor through its POZ domain (first 245 residues); dSAP18 and GAGA co-localize on polytene chromosomes at silenced polycomb response elements of the bithorax complex; reduction of dSAP18 dose in a sensitized background causes homeotic transformation, indicating functional contribution to iab-6 regulation.","method":"Yeast two-hybrid, GST pull-down with recombinant proteins and nuclear extracts, polytene chromosome immunostaining, genetic interaction (dose reduction)","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — GST pull-down with recombinant proteins and crude extracts, chromosomal co-localization, and genetic epistasis in vivo, multiple orthogonal methods","pmids":["11256608"],"is_preprint":false},{"year":2001,"finding":"Drosophila SAP18 (dSAP18), a member of the Sin3A/Rpd3 histone deacetylase complex, interacts with Bicoid in yeast and in vitro, and inhibits Bicoid-dependent transcriptional activation in tissue culture cells.","method":"Yeast two-hybrid, in vitro binding assay, tissue culture reporter assay","journal":"Development genes and evolution","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by in vitro binding and functional reporter assay, single lab","pmids":["11455422"],"is_preprint":false},{"year":2005,"finding":"Drosophila Sap18, as part of the Sin3/Rpd3 histone deacetylase complex, is required for Bicoid-dependent retraction of hunchback expression in the labral region; loss of maternal sap18 in sensitized backgrounds causes failure to repress hb, reduced cap 'n' collar expression, and missing labral cephalopharyngeal skeleton. Phenotypes are enhanced by reducing rpd3 (the catalytic deacetylase subunit), placing Sap18 genetically upstream of/co-operative with Rpd3.","method":"Genetic loss-of-function (maternal sap18 removal), epistasis with rpd3 mutant, in situ hybridization for target gene expression","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic loss-of-function with specific molecular phenotype (hb repression failure), genetic epistasis with rpd3, replicated across multiple mutant backgrounds","pmids":["15649476"],"is_preprint":false},{"year":2006,"finding":"The solution structure of SAP18 reveals a ubiquitin-like fold with large loop insertions, supporting its function as a protein-protein adapter module bridging the Sin3-HDAC complex to transcription factors such as Gli, GAGA, and Bicoid.","method":"NMR solution structure determination","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure of the protein with functional validation by structural context; single lab but high-quality structural method","pmids":["17002296"],"is_preprint":false},{"year":2008,"finding":"In Drosophila, SAP18 associates with the gap gene Krüppel (identified by mass spectrometry) and supports Krüppel-dependent transcriptional repression of pair-rule gene enhancers via site-specific histone H3 deacetylation; Krüppel tethers the SAP18-bound HDAC1 complex at distinct enhancer elements.","method":"Mass spectrometry identification of Krüppel-binding proteins, genetic interaction studies, pharmacological (TSA) inhibition, biochemical co-association, histone H3 acetylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — mass spectrometry identification, genetic epistasis, pharmacological and biochemical validation, multiple orthogonal methods","pmids":["19049982"],"is_preprint":false},{"year":2009,"finding":"SAP18 directly binds HIV-1 integrase (IN) and INI1/hSNF5 (in vitro and in vivo); SAP18 and components of the Sin3A-HDAC1 complex are specifically recruited into HIV-1 (but not SIV or HTLV-1) virions in an HIV-1 IN-dependent manner, and the virion-associated HDAC1 is required for efficient early post-entry reverse transcription steps.","method":"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, virion incorporation assay, dominant-negative HDAC1 mutant, RNAi knockdown of HDAC1, fluorescence-based deacetylase activity assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid confirmed by in vitro binding and co-IP; virion recruitment shown by biochemical fractionation; functional requirement demonstrated by dominant-negative mutant and RNAi, multiple orthogonal methods","pmids":["19503603"],"is_preprint":false},{"year":2010,"finding":"Human SAP18 assembles a nuclear speckle-localized splicing regulatory multiprotein complex (ASAP complex: RNPS1 and Acinus) via its ubiquitin-like fold; SAP18 strongly modulates splicing regulation, and mutational disruption of the ubiquitin-like fold abolishes this splicing regulatory activity.","method":"Splicing reporter assay, mutational analysis of ubiquitin-like fold, co-immunoprecipitation, immunofluorescence (nuclear speckle localization), 3D structural modeling","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP for complex assembly, mutagenesis linking structure to function, functional splicing assay, and localization; multiple orthogonal methods in single study","pmids":["20966198"],"is_preprint":false},{"year":2002,"finding":"The second largest subunit of mouse DNA polymerase epsilon (DPE2) interacts with SAP18 via its N-terminal region (amino acids 85–250); this interaction recruits the Sin3 co-repressor to DNA and causes transcriptional repression that is sensitive to the HDAC inhibitor trichostatin A.","method":"Yeast two-hybrid, domain mapping, transcriptional reporter assay, trichostatin A pharmacological inhibition","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus functional reporter assay and pharmacological evidence; no reciprocal co-IP or in vitro binding to confirm direct interaction","pmids":["11872158"],"is_preprint":false},{"year":2007,"finding":"Chick Hairy1 (a hairy-enhancer-of-split family transcriptional repressor) interacts with Sap18 at its C-terminal portion, confirmed by co-immunoprecipitation; sap18 and sin3a are co-expressed with hairy1 in the rostral presomitic mesoderm and caudal somites, consistent with Hairy1 mediating repression by recruiting Sin3/HDAC via Sap18.","method":"Yeast two-hybrid, co-immunoprecipitation, in situ hybridization for co-expression","journal":"BMC developmental biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid confirmed by co-IP; co-expression shown but no direct functional loss-of-function; two methods, single lab","pmids":["17623094"],"is_preprint":false},{"year":2019,"finding":"The KSHV oncogenic protein vFLIP degrades SAP18 via the ubiquitin-proteasome pathway by recruiting E3 ubiquitin ligase TRIM56; loss of the SAP18/HDAC1 complex impairs its interaction with p65/RelA, leading to enhanced p65 acetylation, NF-κB activation, and promotion of cell invasion and angiogenesis.","method":"Ubiquitin-proteasome pathway assay, co-immunoprecipitation, p65 acetylation assay, NF-κB reporter assay, cell invasion/angiogenesis assay","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays (ubiquitination, co-IP, acetylation) plus functional cellular readouts; single lab","pmids":["30670829"],"is_preprint":false},{"year":2019,"finding":"CXCR2 deficiency in tumor-bearing mice increases SAP18 expression in GMPs, which reduces STAT3 phosphorylation by restraining ERK1/2 activation, thereby decreasing monocytic MDSC expansion; SAP18 acts as a negative regulator in the CXCR2/ERK/STAT3 signaling axis controlling myeloid differentiation.","method":"CXCR2 knockout mouse model, flow cytometry for GMP/MDSC populations, phospho-STAT3 and phospho-ERK1/2 western blot, SAP18 expression analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout model with defined molecular phenotype (ERK/STAT3 phosphorylation) and cellular readout (MDSC differentiation); single lab, pathway placement by genetic epistasis","pmids":["31395859"],"is_preprint":false},{"year":2020,"finding":"Direct interaction of a C21-steroidal compound (A671) with SAP18 stabilizes and activates SAP18, leading to transcriptional suppression of SIRT3 and subsequent inhibition of lymphoma cell proliferation; this defines a SAP18-SIN3-SIRT3 functional axis.","method":"Direct compound-protein interaction assay, SAP18 activation/stability assay, SIRT3 transcription reporter, cell proliferation and viability assay, preclinical mouse model","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct compound-SAP18 interaction with functional downstream readout (SIRT3 suppression, cell death); single lab with multiple assays","pmids":["33273692"],"is_preprint":false},{"year":2010,"finding":"Drosophila dSAP18 co-localizes with histone H3 phosphorylation marks; loss of dSAP18 in mutant embryos disrupts expression of immune and stress response genes; dsap18 mutant larvae develop melanotic tumors after heat shock and show reduced viability after infection or salt stress, indicating dSAP18 is required for transcriptional stress responses.","method":"Genome-wide expression profiling of dsap18 mutant embryos, immunostaining for histone H3 phosphorylation co-localization, genetic loss-of-function with stress phenotype readouts","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with specific molecular phenotype (altered gene expression) and organismal stress phenotypes; co-localization with H3P mark; single lab","pmids":["21146528"],"is_preprint":false},{"year":2024,"finding":"SAP18 interacts with PEDV nonstructural protein Nsp10 (confirmed by IP-MS and co-immunoprecipitation); Nsp10 reduces SAP18 protein levels and induces its cytoplasmic redistribution. SAP18 overexpression suppresses PEDV replication; mechanistically, SAP18 interacts with phosphatase PP1 catalytic subunit alpha (PPP1CA) and promotes PPP1CA-RIG-I interaction, leading to RIG-I dephosphorylation, IRF3/NF-κB phosphorylation, nuclear translocation, and IFN-β antiviral response.","method":"Immunoprecipitation-mass spectrometry (IP-MS), co-immunoprecipitation, laser confocal microscopy (localization), siRNA knockdown, overexpression, phosphorylation and nuclear translocation assays","journal":"Veterinary microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS confirmed by co-IP and functional assays (knockdown/overexpression, phosphorylation); localization shown; single lab, multiple orthogonal methods","pmids":["38795403"],"is_preprint":false},{"year":2024,"finding":"BioID proximity mapping of SAP18 in vivo reveals novel interactions with SIN3 complex components (RBBP4, SAP30BP) and 72 spliceosomal proteins; complementary co-immunoprecipitation validated direct interactions with prespliceosomal components SNRNP70, SNRPA, SF3B1, U2AF1, and SRSF1; a C-terminal SAP18 double point mutant deficient in ASAP interaction shows debilitated interaction with prespliceosomal proteins, linking the ASAP interface to prespliceosome association.","method":"BioID proximity labeling, mass spectrometry, co-immunoprecipitation, mutational analysis (C-terminal double point mutant)","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BioID complemented by reciprocal co-IP and mutagenesis; single lab, multiple orthogonal methods","pmids":["39522233"],"is_preprint":false}],"current_model":"SAP18 is a ubiquitin-fold adapter protein that operates in at least two distinct nuclear complexes: (1) the mSin3-HDAC corepressor complex, where it directly binds mSin3 and bridges transcription factors (Gli, GAGA, Bicoid, Krüppel, Hairy1, Su(fu), DPE2) to the complex to mediate locus-specific histone deacetylation and transcriptional repression; and (2) the ASAP/EJC-associated splicing complex (with RNPS1 and Acinus), where its ubiquitin-like fold assembles a nuclear speckle-localized multiprotein complex that regulates alternative splicing and suppresses cryptic splice sites, with additional roles in prespliceosome association; SAP18 also participates in innate antiviral immunity by facilitating RIG-I dephosphorylation through PP1α and can be recruited into HIV-1 virions via integrase-INI1, where virion-associated HDAC activity is required for early reverse transcription."},"narrative":{"mechanistic_narrative":"SAP18 is a ubiquitin-fold adapter protein that bridges the mSin3-HDAC corepressor complex to sequence-specific transcription factors to mediate locus-specific histone deacetylation and transcriptional repression [PMID:9150135, PMID:17002296]. First identified as a component of the mSin3 complex (containing HDAC1, HDAC2, and SAP30) that directly binds mSin3 and represses transcription when tethered to a promoter [PMID:9150135], its NMR structure revealed a ubiquitin-like fold with large loop insertions that functions as a protein-protein adapter module [PMID:17002296]. Through this interface SAP18 is recruited to specific loci by a range of transcription factors and repressors, including Su(fu)/Gli [PMID:11960000, PMID:14611647], GAGA at polycomb response elements [PMID:11256608], Bicoid [PMID:11455422, PMID:15649476], Krüppel at pair-rule enhancers [PMID:19049982], and Hairy1 [PMID:17623094], in each case delivering Rpd3/HDAC catalytic activity to drive site-specific histone H3 deacetylation and developmental gene repression [PMID:15649476, PMID:19049982]. Independently, the same ubiquitin-like fold assembles the nuclear speckle-localized ASAP splicing complex with RNPS1 and Acinus, where mutational disruption of the fold abolishes splicing regulatory activity [PMID:20966198], and the ASAP interface couples SAP18 to prespliceosomal components including SNRNP70, SF3B1, U2AF1, and SRSF1 [PMID:39522233]. SAP18 also contributes to antiviral innate immunity by interacting with the phosphatase catalytic subunit PPP1CA to promote RIG-I dephosphorylation and downstream IRF3/NF-κB activation and IFN-β induction [PMID:38795403], and is recruited together with the Sin3A-HDAC1 complex into HIV-1 virions via integrase and INI1, where virion-associated HDAC1 activity supports early reverse transcription [PMID:19503603].","teleology":[{"year":1997,"claim":"Established SAP18 as a bona fide subunit of the mSin3-HDAC corepressor complex and a direct transcriptional repressor, defining its founding biochemical context.","evidence":"Co-immunoprecipitation, cDNA cloning, and in vivo reporter tethering assay in mammalian cells","pmids":["9150135"],"confidence":"High","gaps":["Did not reveal how SAP18 is recruited to specific genomic loci","No structural basis for the mSin3 interaction"]},{"year":2001,"claim":"Showed SAP18 is a conserved Sin3A/Rpd3 complex member that links specific activators/repressors to deacetylation, beginning to explain locus-specific targeting.","evidence":"Drosophila yeast two-hybrid, in vitro binding, and tissue-culture reporter assays with Bicoid; GAGA POZ-domain pull-downs and polytene co-localization","pmids":["11455422","11256608"],"confidence":"High","gaps":["Direct demonstration of HDAC catalytic recruitment at target loci not yet shown in vivo"]},{"year":2002,"claim":"Extended the adapter model by identifying Su(fu) and DNA polymerase epsilon subunit DPE2 as factors that recruit SAP18-Sin3 to Gli-responsive and other promoters.","evidence":"Co-immunoprecipitation, promoter recruitment, reporter assays, and yeast two-hybrid with TSA sensitivity","pmids":["11960000","11872158"],"confidence":"Medium","gaps":["DPE2 interaction not confirmed by reciprocal co-IP or in vitro binding","Physiological relevance of polymerase-linked repression unclear"]},{"year":2005,"claim":"Provided clean genetic loss-of-function evidence placing SAP18 cooperatively with the catalytic deacetylase Rpd3 in developmental repression, moving beyond correlative binding.","evidence":"Maternal sap18 removal, epistasis with rpd3, and in situ hybridization for hunchback/cnc target genes in Drosophila","pmids":["15649476"],"confidence":"High","gaps":["Mechanism of Bicoid-to-SAP18 handoff at specific enhancers not resolved at molecular detail"]},{"year":2006,"claim":"Determined the SAP18 solution structure, revealing a ubiquitin-like fold with loop insertions that rationalizes its function as a protein-protein adapter.","evidence":"NMR solution structure determination","pmids":["17002296"],"confidence":"High","gaps":["No co-structure with mSin3 or any partner","Fold-to-partner contact residues not mapped experimentally in this study"]},{"year":2008,"claim":"Demonstrated that a specific gap-gene repressor (Krüppel) tethers the SAP18-HDAC1 complex to distinct enhancers, directly linking SAP18 to site-specific H3 deacetylation.","evidence":"Mass spectrometry, genetic interactions, TSA inhibition, and histone H3 acetylation assays in Drosophila","pmids":["19049982"],"confidence":"High","gaps":["How multiple transcription factors compete for or share the same SAP18 surface remains unknown"]},{"year":2009,"claim":"Revealed a non-transcriptional, pathogen-exploited role: HIV-1 integrase/INI1 recruits SAP18 and the Sin3A-HDAC1 complex into virions, where HDAC1 activity supports early reverse transcription.","evidence":"Yeast two-hybrid, in vitro binding, co-IP, virion incorporation assays, dominant-negative HDAC1, and RNAi in HIV-1 systems","pmids":["19503603"],"confidence":"High","gaps":["Molecular role of deacetylation in reverse transcription not defined","Whether SAP18's transcriptional and virion functions use the same interface unclear"]},{"year":2010,"claim":"Established a second, mechanistically distinct nuclear function: the ubiquitin-like fold assembles the nuclear-speckle ASAP splicing complex with RNPS1 and Acinus to regulate splicing.","evidence":"Splicing reporter assays, ubiquitin-like fold mutagenesis, co-IP, immunofluorescence, and structural modeling in human cells","pmids":["20966198"],"confidence":"High","gaps":["How SAP18 partitions between Sin3-HDAC and ASAP complexes not determined","Direct RNA-binding role not established"]},{"year":2019,"claim":"Identified SAP18 as a regulatory node co-opted in disease: KSHV vFLIP drives its TRIM56-dependent degradation to derepress NF-κB, and SAP18 restrains the CXCR2/ERK/STAT3 myeloid differentiation axis.","evidence":"Ubiquitination and acetylation assays, NF-κB reporters, and CXCR2 knockout mouse with phospho-STAT3/ERK readouts","pmids":["30670829","31395859"],"confidence":"Medium","gaps":["Direct versus indirect control of p65 acetylation by the SAP18/HDAC1 complex not fully separated","Mechanism of SAP18 action in GMPs is correlative"]},{"year":2024,"claim":"Resolved an antiviral immune mechanism and refined the splicing interactome: SAP18 bridges PPP1CA to RIG-I for dephosphorylation-driven IFN-β induction, and the ASAP interface couples it to prespliceosomal factors.","evidence":"IP-MS, co-IP, confocal localization and phospho/translocation assays (PEDV/RIG-I); BioID and reciprocal co-IP with spliceosomal proteins","pmids":["38795403","39522233"],"confidence":"Medium","gaps":["Direct ternary PPP1CA-SAP18-RIG-I complex not structurally validated","Functional consequence of prespliceosome association on specific transcripts not mapped"]},{"year":null,"claim":"How SAP18 is partitioned among its mSin3-HDAC, ASAP/spliceosomal, and phosphatase-bridging roles, and whether a single ubiquitin-like surface is shared or competed for by these mutually exclusive partners, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model distinguishing the binding modes for transcription factors versus ASAP versus PPP1CA","No quantitative measure of complex stoichiometry or exchange in cells"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,6,9]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,5,7]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[9,17]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,5,7]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[9,17]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,6,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[16]}],"complexes":["mSin3-HDAC corepressor complex","ASAP complex (SAP18-RNPS1-Acinus)"],"partners":["SIN3A","HDAC1","RNPS1","ACINUS","SF3B1","SNRNP70","PPP1CA","SU(FU)"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00422","full_name":"Histone deacetylase complex subunit SAP18","aliases":["18 kDa Sin3-associated polypeptide","2HOR0202","Cell growth-inhibiting gene 38 protein","Sin3-associated polypeptide p18"],"length_aa":153,"mass_kda":17.6,"function":"Component of the SIN3-repressing complex. Enhances the ability of SIN3-HDAC1-mediated transcriptional repression. When tethered to the promoter, it can direct the formation of a repressive complex to core histone proteins. Auxiliary component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junction on mRNAs. The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. Component of the ASAP and PSAP complexes which bind RNA in a sequence-independent manner and are proposed to be recruited to the EJC prior to or during the splicing process and to regulate specific excision of introns in specific transcription subsets. The ASAP complex can inhibit mRNA processing during in vitro splicing reactions. The ASAP complex promotes apoptosis and is disassembled after induction of apoptosis. Involved in the splicing modulation of BCL2L1/Bcl-X (and probably other apoptotic genes); specifically inhibits the formation of proapoptotic isoforms such as Bcl-X(S); the activity is different from the established EJC assembly and function","subcellular_location":"Nucleus; Cytoplasm; Nucleus speckle","url":"https://www.uniprot.org/uniprotkb/O00422/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SAP18","classification":"Common Essential","n_dependent_lines":1182,"n_total_lines":1208,"dependency_fraction":0.9784768211920529},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RBM42","stoichiometry":10.0},{"gene":"RBM33","stoichiometry":4.0},{"gene":"CALD1","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX39B","stoichiometry":0.2},{"gene":"MMGT1","stoichiometry":0.2},{"gene":"PRPF4B","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2},{"gene":"RBM8A","stoichiometry":0.2},{"gene":"RTCB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SAP18","total_profiled":1310},"omim":[{"mim_id":"609906","title":"EMBRYONAL FYN-ASSOCIATED SUBSTRATE; EFS","url":"https://www.omim.org/entry/609906"},{"mim_id":"605164","title":"HISTONE DEACETYLASE 2; HDAC2","url":"https://www.omim.org/entry/605164"},{"mim_id":"603378","title":"SIN3-ASSOCIATED POLYPEPTIDE, 30-KD; SAP30","url":"https://www.omim.org/entry/603378"},{"mim_id":"602949","title":"SIN3-ASSOCIATED POLYPEPTIDE, 18-KD; SAP18","url":"https://www.omim.org/entry/602949"},{"mim_id":"601241","title":"HISTONE DEACETYLASE 1; HDAC1","url":"https://www.omim.org/entry/601241"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SAP18"},"hgnc":{"alias_symbol":["SAP18p","2HOR0202","MGC27131"],"prev_symbol":[]},"alphafold":{"accession":"O00422","domains":[{"cath_id":"3.10.20.550","chopping":"27-137","consensus_level":"high","plddt":95.4875,"start":27,"end":137}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00422","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00422-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00422-F1-predicted_aligned_error_v6.png","plddt_mean":87.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SAP18","jax_strain_url":"https://www.jax.org/strain/search?query=SAP18"},"sequence":{"accession":"O00422","fasta_url":"https://rest.uniprot.org/uniprotkb/O00422.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00422/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00422"}},"corpus_meta":[{"pmid":"9150135","id":"PMC_9150135","title":"Histone deacetylases and SAP18, a novel polypeptide, are components of a human Sin3 complex.","date":"1997","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/9150135","citation_count":506,"is_preprint":false},{"pmid":"11960000","id":"PMC_11960000","title":"Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11960000","citation_count":180,"is_preprint":false},{"pmid":"14611647","id":"PMC_14611647","title":"The negative regulator of Gli, Suppressor of fused (Sufu), interacts with SAP18, Galectin3 and other nuclear proteins.","date":"2004","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/14611647","citation_count":93,"is_preprint":false},{"pmid":"11256608","id":"PMC_11256608","title":"The GAGA factor of Drosophila interacts with SAP18, a Sin3-associated polypeptide.","date":"2000","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/11256608","citation_count":54,"is_preprint":false},{"pmid":"19503603","id":"PMC_19503603","title":"Recruitment of a SAP18-HDAC1 complex into HIV-1 virions and its requirement for viral replication.","date":"2009","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/19503603","citation_count":52,"is_preprint":false},{"pmid":"31395859","id":"PMC_31395859","title":"CXCR2 expression on granulocyte and macrophage progenitors under tumor conditions contributes to mo-MDSC generation via SAP18/ERK/STAT3.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31395859","citation_count":51,"is_preprint":false},{"pmid":"20966198","id":"PMC_20966198","title":"Human SAP18 mediates assembly of a splicing regulatory multiprotein complex via its ubiquitin-like fold.","date":"2010","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/20966198","citation_count":42,"is_preprint":false},{"pmid":"30670829","id":"PMC_30670829","title":"Suppression of the SAP18/HDAC1 complex by targeting TRIM56 and Nanog is essential for oncogenic viral FLICE-inhibitory protein-induced acetylation of p65/RelA, NF-κB activation, and promotion of cell invasion and angiogenesis.","date":"2019","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/30670829","citation_count":40,"is_preprint":false},{"pmid":"11455422","id":"PMC_11455422","title":"Drosophila SAP18, a member of the Sin3/Rpd3 histone deacetylase complex, interacts with Bicoid and inhibits its activity.","date":"2001","source":"Development genes and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/11455422","citation_count":30,"is_preprint":false},{"pmid":"15649476","id":"PMC_15649476","title":"Sap18 is required for the maternal gene bicoid to direct anterior patterning in Drosophila melanogaster.","date":"2005","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/15649476","citation_count":24,"is_preprint":false},{"pmid":"9511770","id":"PMC_9511770","title":"Cloning of the murine transcriptional corepressor component SAP18 and differential expression of its mRNA in the hematopoietic hierarchy.","date":"1998","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/9511770","citation_count":19,"is_preprint":false},{"pmid":"11872158","id":"PMC_11872158","title":"The second largest subunit of mouse DNA polymerase epsilon, DPE2, interacts with SAP18 and recruits the Sin3 co-repressor protein to DNA.","date":"2002","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11872158","citation_count":16,"is_preprint":false},{"pmid":"17002296","id":"PMC_17002296","title":"Structure of SAP18: a ubiquitin fold in histone deacetylase complex 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letters","url":"https://pubmed.ncbi.nlm.nih.gov/21146528","citation_count":10,"is_preprint":false},{"pmid":"19049982","id":"PMC_19049982","title":"SAP18 promotes Krüppel-dependent transcriptional repression by enhancer-specific histone deacetylation.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19049982","citation_count":8,"is_preprint":false},{"pmid":"17623094","id":"PMC_17623094","title":"Chick Hairy1 protein interacts with Sap18, a component of the Sin3/HDAC transcriptional repressor complex.","date":"2007","source":"BMC developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/17623094","citation_count":6,"is_preprint":false},{"pmid":"38795403","id":"PMC_38795403","title":"Nsp10-interacting host protein SAP18 restricts PEDV replication in Marc-145 cells via enhancing dephosphorylation of RIG-I.","date":"2024","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/38795403","citation_count":3,"is_preprint":false},{"pmid":"31488810","id":"PMC_31488810","title":"Correction: CXCR2 expression on granulocyte and macrophage progenitors under tumor conditions contributes to mo-MDSC generation via SAP18/ERK/STAT3.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31488810","citation_count":3,"is_preprint":false},{"pmid":"39522233","id":"PMC_39522233","title":"BioID proximity mapping reveals novel SAP18 interactions in the prespliceosomal complex.","date":"2024","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/39522233","citation_count":2,"is_preprint":false},{"pmid":"41109507","id":"PMC_41109507","title":"Plant responses to full moonlight requires the SUVH4 HMTase which may target active genes via interaction with the splicing factor SAP18.","date":"2025","source":"Plant science : an international journal of experimental plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/41109507","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11417,"output_tokens":4708,"usd":0.052436,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12866,"output_tokens":3768,"usd":0.079265,"stage2_stop_reason":"end_turn"},"total_usd":0.131701,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"SAP18 is a component of the mammalian Sin3 (mSin3) complex that also contains HDAC1, HDAC2, and SAP30. SAP18 directly interacts with mSin3, and when tethered to a promoter, SAP18 represses transcription in vivo.\",\n      \"method\": \"Co-immunoprecipitation, cDNA cloning, in vivo transcription reporter assay, direct interaction demonstrated biochemically\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, in vivo reporter assay, direct interaction confirmed; foundational paper replicated by multiple subsequent studies\",\n      \"pmids\": [\"9150135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mouse Suppressor of Fused [mSu(fu)] specifically interacts with SAP18 and functionally cooperates with SAP18 to repress Gli-mediated transcription by recruiting the SAP18-mSin3 complex to promoters containing Gli-binding elements.\",\n      \"method\": \"Co-immunoprecipitation, in vivo transcription reporter assay, promoter recruitment assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus functional reporter assay, single lab with two orthogonal methods\",\n      \"pmids\": [\"11960000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"mSufu interacts with SAP18 (confirmed by independent biochemical assays beyond yeast two-hybrid), and co-expression of SAP18 (normally nuclear) causes translocation of predominantly cytoplasmic mSufu to the nucleus.\",\n      \"method\": \"Yeast two-hybrid, independent biochemical co-immunoprecipitation, cell transfection/localization assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction confirmed by independent biochemical assay; localization consequence shown by co-expression, single lab\",\n      \"pmids\": [\"14611647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Drosophila SAP18 (dSAP18) interacts with the GAGA factor through its POZ domain (first 245 residues); dSAP18 and GAGA co-localize on polytene chromosomes at silenced polycomb response elements of the bithorax complex; reduction of dSAP18 dose in a sensitized background causes homeotic transformation, indicating functional contribution to iab-6 regulation.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down with recombinant proteins and nuclear extracts, polytene chromosome immunostaining, genetic interaction (dose reduction)\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — GST pull-down with recombinant proteins and crude extracts, chromosomal co-localization, and genetic epistasis in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"11256608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Drosophila SAP18 (dSAP18), a member of the Sin3A/Rpd3 histone deacetylase complex, interacts with Bicoid in yeast and in vitro, and inhibits Bicoid-dependent transcriptional activation in tissue culture cells.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, tissue culture reporter assay\",\n      \"journal\": \"Development genes and evolution\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by in vitro binding and functional reporter assay, single lab\",\n      \"pmids\": [\"11455422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Drosophila Sap18, as part of the Sin3/Rpd3 histone deacetylase complex, is required for Bicoid-dependent retraction of hunchback expression in the labral region; loss of maternal sap18 in sensitized backgrounds causes failure to repress hb, reduced cap 'n' collar expression, and missing labral cephalopharyngeal skeleton. Phenotypes are enhanced by reducing rpd3 (the catalytic deacetylase subunit), placing Sap18 genetically upstream of/co-operative with Rpd3.\",\n      \"method\": \"Genetic loss-of-function (maternal sap18 removal), epistasis with rpd3 mutant, in situ hybridization for target gene expression\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic loss-of-function with specific molecular phenotype (hb repression failure), genetic epistasis with rpd3, replicated across multiple mutant backgrounds\",\n      \"pmids\": [\"15649476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The solution structure of SAP18 reveals a ubiquitin-like fold with large loop insertions, supporting its function as a protein-protein adapter module bridging the Sin3-HDAC complex to transcription factors such as Gli, GAGA, and Bicoid.\",\n      \"method\": \"NMR solution structure determination\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure of the protein with functional validation by structural context; single lab but high-quality structural method\",\n      \"pmids\": [\"17002296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In Drosophila, SAP18 associates with the gap gene Krüppel (identified by mass spectrometry) and supports Krüppel-dependent transcriptional repression of pair-rule gene enhancers via site-specific histone H3 deacetylation; Krüppel tethers the SAP18-bound HDAC1 complex at distinct enhancer elements.\",\n      \"method\": \"Mass spectrometry identification of Krüppel-binding proteins, genetic interaction studies, pharmacological (TSA) inhibition, biochemical co-association, histone H3 acetylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mass spectrometry identification, genetic epistasis, pharmacological and biochemical validation, multiple orthogonal methods\",\n      \"pmids\": [\"19049982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SAP18 directly binds HIV-1 integrase (IN) and INI1/hSNF5 (in vitro and in vivo); SAP18 and components of the Sin3A-HDAC1 complex are specifically recruited into HIV-1 (but not SIV or HTLV-1) virions in an HIV-1 IN-dependent manner, and the virion-associated HDAC1 is required for efficient early post-entry reverse transcription steps.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, virion incorporation assay, dominant-negative HDAC1 mutant, RNAi knockdown of HDAC1, fluorescence-based deacetylase activity assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid confirmed by in vitro binding and co-IP; virion recruitment shown by biochemical fractionation; functional requirement demonstrated by dominant-negative mutant and RNAi, multiple orthogonal methods\",\n      \"pmids\": [\"19503603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human SAP18 assembles a nuclear speckle-localized splicing regulatory multiprotein complex (ASAP complex: RNPS1 and Acinus) via its ubiquitin-like fold; SAP18 strongly modulates splicing regulation, and mutational disruption of the ubiquitin-like fold abolishes this splicing regulatory activity.\",\n      \"method\": \"Splicing reporter assay, mutational analysis of ubiquitin-like fold, co-immunoprecipitation, immunofluorescence (nuclear speckle localization), 3D structural modeling\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP for complex assembly, mutagenesis linking structure to function, functional splicing assay, and localization; multiple orthogonal methods in single study\",\n      \"pmids\": [\"20966198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The second largest subunit of mouse DNA polymerase epsilon (DPE2) interacts with SAP18 via its N-terminal region (amino acids 85–250); this interaction recruits the Sin3 co-repressor to DNA and causes transcriptional repression that is sensitive to the HDAC inhibitor trichostatin A.\",\n      \"method\": \"Yeast two-hybrid, domain mapping, transcriptional reporter assay, trichostatin A pharmacological inhibition\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus functional reporter assay and pharmacological evidence; no reciprocal co-IP or in vitro binding to confirm direct interaction\",\n      \"pmids\": [\"11872158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Chick Hairy1 (a hairy-enhancer-of-split family transcriptional repressor) interacts with Sap18 at its C-terminal portion, confirmed by co-immunoprecipitation; sap18 and sin3a are co-expressed with hairy1 in the rostral presomitic mesoderm and caudal somites, consistent with Hairy1 mediating repression by recruiting Sin3/HDAC via Sap18.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in situ hybridization for co-expression\",\n      \"journal\": \"BMC developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid confirmed by co-IP; co-expression shown but no direct functional loss-of-function; two methods, single lab\",\n      \"pmids\": [\"17623094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The KSHV oncogenic protein vFLIP degrades SAP18 via the ubiquitin-proteasome pathway by recruiting E3 ubiquitin ligase TRIM56; loss of the SAP18/HDAC1 complex impairs its interaction with p65/RelA, leading to enhanced p65 acetylation, NF-κB activation, and promotion of cell invasion and angiogenesis.\",\n      \"method\": \"Ubiquitin-proteasome pathway assay, co-immunoprecipitation, p65 acetylation assay, NF-κB reporter assay, cell invasion/angiogenesis assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays (ubiquitination, co-IP, acetylation) plus functional cellular readouts; single lab\",\n      \"pmids\": [\"30670829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CXCR2 deficiency in tumor-bearing mice increases SAP18 expression in GMPs, which reduces STAT3 phosphorylation by restraining ERK1/2 activation, thereby decreasing monocytic MDSC expansion; SAP18 acts as a negative regulator in the CXCR2/ERK/STAT3 signaling axis controlling myeloid differentiation.\",\n      \"method\": \"CXCR2 knockout mouse model, flow cytometry for GMP/MDSC populations, phospho-STAT3 and phospho-ERK1/2 western blot, SAP18 expression analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout model with defined molecular phenotype (ERK/STAT3 phosphorylation) and cellular readout (MDSC differentiation); single lab, pathway placement by genetic epistasis\",\n      \"pmids\": [\"31395859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Direct interaction of a C21-steroidal compound (A671) with SAP18 stabilizes and activates SAP18, leading to transcriptional suppression of SIRT3 and subsequent inhibition of lymphoma cell proliferation; this defines a SAP18-SIN3-SIRT3 functional axis.\",\n      \"method\": \"Direct compound-protein interaction assay, SAP18 activation/stability assay, SIRT3 transcription reporter, cell proliferation and viability assay, preclinical mouse model\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct compound-SAP18 interaction with functional downstream readout (SIRT3 suppression, cell death); single lab with multiple assays\",\n      \"pmids\": [\"33273692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Drosophila dSAP18 co-localizes with histone H3 phosphorylation marks; loss of dSAP18 in mutant embryos disrupts expression of immune and stress response genes; dsap18 mutant larvae develop melanotic tumors after heat shock and show reduced viability after infection or salt stress, indicating dSAP18 is required for transcriptional stress responses.\",\n      \"method\": \"Genome-wide expression profiling of dsap18 mutant embryos, immunostaining for histone H3 phosphorylation co-localization, genetic loss-of-function with stress phenotype readouts\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with specific molecular phenotype (altered gene expression) and organismal stress phenotypes; co-localization with H3P mark; single lab\",\n      \"pmids\": [\"21146528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SAP18 interacts with PEDV nonstructural protein Nsp10 (confirmed by IP-MS and co-immunoprecipitation); Nsp10 reduces SAP18 protein levels and induces its cytoplasmic redistribution. SAP18 overexpression suppresses PEDV replication; mechanistically, SAP18 interacts with phosphatase PP1 catalytic subunit alpha (PPP1CA) and promotes PPP1CA-RIG-I interaction, leading to RIG-I dephosphorylation, IRF3/NF-κB phosphorylation, nuclear translocation, and IFN-β antiviral response.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry (IP-MS), co-immunoprecipitation, laser confocal microscopy (localization), siRNA knockdown, overexpression, phosphorylation and nuclear translocation assays\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS confirmed by co-IP and functional assays (knockdown/overexpression, phosphorylation); localization shown; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38795403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BioID proximity mapping of SAP18 in vivo reveals novel interactions with SIN3 complex components (RBBP4, SAP30BP) and 72 spliceosomal proteins; complementary co-immunoprecipitation validated direct interactions with prespliceosomal components SNRNP70, SNRPA, SF3B1, U2AF1, and SRSF1; a C-terminal SAP18 double point mutant deficient in ASAP interaction shows debilitated interaction with prespliceosomal proteins, linking the ASAP interface to prespliceosome association.\",\n      \"method\": \"BioID proximity labeling, mass spectrometry, co-immunoprecipitation, mutational analysis (C-terminal double point mutant)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID complemented by reciprocal co-IP and mutagenesis; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39522233\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SAP18 is a ubiquitin-fold adapter protein that operates in at least two distinct nuclear complexes: (1) the mSin3-HDAC corepressor complex, where it directly binds mSin3 and bridges transcription factors (Gli, GAGA, Bicoid, Krüppel, Hairy1, Su(fu), DPE2) to the complex to mediate locus-specific histone deacetylation and transcriptional repression; and (2) the ASAP/EJC-associated splicing complex (with RNPS1 and Acinus), where its ubiquitin-like fold assembles a nuclear speckle-localized multiprotein complex that regulates alternative splicing and suppresses cryptic splice sites, with additional roles in prespliceosome association; SAP18 also participates in innate antiviral immunity by facilitating RIG-I dephosphorylation through PP1α and can be recruited into HIV-1 virions via integrase-INI1, where virion-associated HDAC activity is required for early reverse transcription.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SAP18 is a ubiquitin-fold adapter protein that bridges the mSin3-HDAC corepressor complex to sequence-specific transcription factors to mediate locus-specific histone deacetylation and transcriptional repression [#0, #6]. First identified as a component of the mSin3 complex (containing HDAC1, HDAC2, and SAP30) that directly binds mSin3 and represses transcription when tethered to a promoter [#0], its NMR structure revealed a ubiquitin-like fold with large loop insertions that functions as a protein-protein adapter module [#6]. Through this interface SAP18 is recruited to specific loci by a range of transcription factors and repressors, including Su(fu)/Gli [#1, #2], GAGA at polycomb response elements [#3], Bicoid [#4, #5], Krüppel at pair-rule enhancers [#7], and Hairy1 [#11], in each case delivering Rpd3/HDAC catalytic activity to drive site-specific histone H3 deacetylation and developmental gene repression [#5, #7]. Independently, the same ubiquitin-like fold assembles the nuclear speckle-localized ASAP splicing complex with RNPS1 and Acinus, where mutational disruption of the fold abolishes splicing regulatory activity [#9], and the ASAP interface couples SAP18 to prespliceosomal components including SNRNP70, SF3B1, U2AF1, and SRSF1 [#17]. SAP18 also contributes to antiviral innate immunity by interacting with the phosphatase catalytic subunit PPP1CA to promote RIG-I dephosphorylation and downstream IRF3/NF-\\u03baB activation and IFN-\\u03b2 induction [#16], and is recruited together with the Sin3A-HDAC1 complex into HIV-1 virions via integrase and INI1, where virion-associated HDAC1 activity supports early reverse transcription [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established SAP18 as a bona fide subunit of the mSin3-HDAC corepressor complex and a direct transcriptional repressor, defining its founding biochemical context.\",\n      \"evidence\": \"Co-immunoprecipitation, cDNA cloning, and in vivo reporter tethering assay in mammalian cells\",\n      \"pmids\": [\"9150135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not reveal how SAP18 is recruited to specific genomic loci\", \"No structural basis for the mSin3 interaction\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed SAP18 is a conserved Sin3A/Rpd3 complex member that links specific activators/repressors to deacetylation, beginning to explain locus-specific targeting.\",\n      \"evidence\": \"Drosophila yeast two-hybrid, in vitro binding, and tissue-culture reporter assays with Bicoid; GAGA POZ-domain pull-downs and polytene co-localization\",\n      \"pmids\": [\"11455422\", \"11256608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration of HDAC catalytic recruitment at target loci not yet shown in vivo\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Extended the adapter model by identifying Su(fu) and DNA polymerase epsilon subunit DPE2 as factors that recruit SAP18-Sin3 to Gli-responsive and other promoters.\",\n      \"evidence\": \"Co-immunoprecipitation, promoter recruitment, reporter assays, and yeast two-hybrid with TSA sensitivity\",\n      \"pmids\": [\"11960000\", \"11872158\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DPE2 interaction not confirmed by reciprocal co-IP or in vitro binding\", \"Physiological relevance of polymerase-linked repression unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Provided clean genetic loss-of-function evidence placing SAP18 cooperatively with the catalytic deacetylase Rpd3 in developmental repression, moving beyond correlative binding.\",\n      \"evidence\": \"Maternal sap18 removal, epistasis with rpd3, and in situ hybridization for hunchback/cnc target genes in Drosophila\",\n      \"pmids\": [\"15649476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Bicoid-to-SAP18 handoff at specific enhancers not resolved at molecular detail\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Determined the SAP18 solution structure, revealing a ubiquitin-like fold with loop insertions that rationalizes its function as a protein-protein adapter.\",\n      \"evidence\": \"NMR solution structure determination\",\n      \"pmids\": [\"17002296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-structure with mSin3 or any partner\", \"Fold-to-partner contact residues not mapped experimentally in this study\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that a specific gap-gene repressor (Krüppel) tethers the SAP18-HDAC1 complex to distinct enhancers, directly linking SAP18 to site-specific H3 deacetylation.\",\n      \"evidence\": \"Mass spectrometry, genetic interactions, TSA inhibition, and histone H3 acetylation assays in Drosophila\",\n      \"pmids\": [\"19049982\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How multiple transcription factors compete for or share the same SAP18 surface remains unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed a non-transcriptional, pathogen-exploited role: HIV-1 integrase/INI1 recruits SAP18 and the Sin3A-HDAC1 complex into virions, where HDAC1 activity supports early reverse transcription.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, co-IP, virion incorporation assays, dominant-negative HDAC1, and RNAi in HIV-1 systems\",\n      \"pmids\": [\"19503603\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular role of deacetylation in reverse transcription not defined\", \"Whether SAP18's transcriptional and virion functions use the same interface unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established a second, mechanistically distinct nuclear function: the ubiquitin-like fold assembles the nuclear-speckle ASAP splicing complex with RNPS1 and Acinus to regulate splicing.\",\n      \"evidence\": \"Splicing reporter assays, ubiquitin-like fold mutagenesis, co-IP, immunofluorescence, and structural modeling in human cells\",\n      \"pmids\": [\"20966198\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SAP18 partitions between Sin3-HDAC and ASAP complexes not determined\", \"Direct RNA-binding role not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified SAP18 as a regulatory node co-opted in disease: KSHV vFLIP drives its TRIM56-dependent degradation to derepress NF-\\u03baB, and SAP18 restrains the CXCR2/ERK/STAT3 myeloid differentiation axis.\",\n      \"evidence\": \"Ubiquitination and acetylation assays, NF-\\u03baB reporters, and CXCR2 knockout mouse with phospho-STAT3/ERK readouts\",\n      \"pmids\": [\"30670829\", \"31395859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect control of p65 acetylation by the SAP18/HDAC1 complex not fully separated\", \"Mechanism of SAP18 action in GMPs is correlative\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved an antiviral immune mechanism and refined the splicing interactome: SAP18 bridges PPP1CA to RIG-I for dephosphorylation-driven IFN-\\u03b2 induction, and the ASAP interface couples it to prespliceosomal factors.\",\n      \"evidence\": \"IP-MS, co-IP, confocal localization and phospho/translocation assays (PEDV/RIG-I); BioID and reciprocal co-IP with spliceosomal proteins\",\n      \"pmids\": [\"38795403\", \"39522233\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ternary PPP1CA-SAP18-RIG-I complex not structurally validated\", \"Functional consequence of prespliceosome association on specific transcripts not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SAP18 is partitioned among its mSin3-HDAC, ASAP/spliceosomal, and phosphatase-bridging roles, and whether a single ubiquitin-like surface is shared or competed for by these mutually exclusive partners, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model distinguishing the binding modes for transcription factors versus ASAP versus PPP1CA\", \"No quantitative measure of complex stoichiometry or exchange in cells\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 6, 9]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [9, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [9, 17]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"complexes\": [\n      \"mSin3-HDAC corepressor complex\",\n      \"ASAP complex (SAP18-RNPS1-Acinus)\"\n    ],\n    \"partners\": [\n      \"SIN3A\",\n      \"HDAC1\",\n      \"RNPS1\",\n      \"Acinus\",\n      \"SF3B1\",\n      \"SNRNP70\",\n      \"PPP1CA\",\n      \"Su(fu)\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}