Affinage

SAP18

Histone deacetylase complex subunit SAP18 · UniProt O00422

Length
153 aa
Mass
17.6 kDa
Annotated
2026-06-10
22 papers in source corpus 18 papers cited in narrative 18 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1997 High

    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

    PMID:9150135

    Open questions at the time
    • Did not reveal how SAP18 is recruited to specific genomic loci
    • No structural basis for the mSin3 interaction
  2. 2001 High

    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

    PMID:11256608 PMID:11455422

    Open questions at the time
    • Direct demonstration of HDAC catalytic recruitment at target loci not yet shown in vivo
  3. 2002 Medium

    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

    PMID:11872158 PMID:11960000

    Open questions at the time
    • DPE2 interaction not confirmed by reciprocal co-IP or in vitro binding
    • Physiological relevance of polymerase-linked repression unclear
  4. 2005 High

    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

    PMID:15649476

    Open questions at the time
    • Mechanism of Bicoid-to-SAP18 handoff at specific enhancers not resolved at molecular detail
  5. 2006 High

    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

    PMID:17002296

    Open questions at the time
    • No co-structure with mSin3 or any partner
    • Fold-to-partner contact residues not mapped experimentally in this study
  6. 2008 High

    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

    PMID:19049982

    Open questions at the time
    • How multiple transcription factors compete for or share the same SAP18 surface remains unknown
  7. 2009 High

    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

    PMID:19503603

    Open questions at the time
    • Molecular role of deacetylation in reverse transcription not defined
    • Whether SAP18's transcriptional and virion functions use the same interface unclear
  8. 2010 High

    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

    PMID:20966198

    Open questions at the time
    • How SAP18 partitions between Sin3-HDAC and ASAP complexes not determined
    • Direct RNA-binding role not established
  9. 2019 Medium

    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

    PMID:30670829 PMID:31395859

    Open questions at the time
    • Direct versus indirect control of p65 acetylation by the SAP18/HDAC1 complex not fully separated
    • Mechanism of SAP18 action in GMPs is correlative
  10. 2024 Medium

    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

    PMID:38795403 PMID:39522233

    Open questions at the time
    • Direct ternary PPP1CA-SAP18-RIG-I complex not structurally validated
    • Functional consequence of prespliceosome association on specific transcripts not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 3 GO:0003723 RNA binding 2
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 1
Pathway
R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-8953854 Metabolism of RNA 2 R-HSA-168256 Immune System 1
Partners
ACINUSHDAC1PPP1CARNPS1SF3B1SIN3ASNRNP70SU(FU)
Complex memberships
ASAP complex (SAP18-RNPS1-Acinus)mSin3-HDAC corepressor complex

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 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. Co-immunoprecipitation, cDNA cloning, in vivo transcription reporter assay, direct interaction demonstrated biochemically Cell High 9150135
2002 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. Co-immunoprecipitation, in vivo transcription reporter assay, promoter recruitment assay Proceedings of the National Academy of Sciences of the United States of America High 11960000
2004 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. Yeast two-hybrid, independent biochemical co-immunoprecipitation, cell transfection/localization assay The Biochemical journal Medium 14611647
2000 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. Yeast two-hybrid, GST pull-down with recombinant proteins and nuclear extracts, polytene chromosome immunostaining, genetic interaction (dose reduction) EMBO reports High 11256608
2001 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. Yeast two-hybrid, in vitro binding assay, tissue culture reporter assay Development genes and evolution Medium 11455422
2005 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. Genetic loss-of-function (maternal sap18 removal), epistasis with rpd3 mutant, in situ hybridization for target gene expression Developmental biology High 15649476
2006 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. NMR solution structure determination Biochemistry High 17002296
2008 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. Mass spectrometry identification of Krüppel-binding proteins, genetic interaction studies, pharmacological (TSA) inhibition, biochemical co-association, histone H3 acetylation assay The Journal of biological chemistry High 19049982
2009 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. 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 PLoS pathogens High 19503603
2010 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. Splicing reporter assay, mutational analysis of ubiquitin-like fold, co-immunoprecipitation, immunofluorescence (nuclear speckle localization), 3D structural modeling RNA (New York, N.Y.) High 20966198
2002 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. Yeast two-hybrid, domain mapping, transcriptional reporter assay, trichostatin A pharmacological inhibition Journal of biochemistry Medium 11872158
2007 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. Yeast two-hybrid, co-immunoprecipitation, in situ hybridization for co-expression BMC developmental biology Medium 17623094
2019 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. Ubiquitin-proteasome pathway assay, co-immunoprecipitation, p65 acetylation assay, NF-κB reporter assay, cell invasion/angiogenesis assay Cell death and differentiation Medium 30670829
2019 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. CXCR2 knockout mouse model, flow cytometry for GMP/MDSC populations, phospho-STAT3 and phospho-ERK1/2 western blot, SAP18 expression analysis Cell death & disease Medium 31395859
2020 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. Direct compound-protein interaction assay, SAP18 activation/stability assay, SIRT3 transcription reporter, cell proliferation and viability assay, preclinical mouse model Communications biology Medium 33273692
2010 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. Genome-wide expression profiling of dsap18 mutant embryos, immunostaining for histone H3 phosphorylation co-localization, genetic loss-of-function with stress phenotype readouts FEBS letters Medium 21146528
2024 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. Immunoprecipitation-mass spectrometry (IP-MS), co-immunoprecipitation, laser confocal microscopy (localization), siRNA knockdown, overexpression, phosphorylation and nuclear translocation assays Veterinary microbiology Medium 38795403
2024 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. BioID proximity labeling, mass spectrometry, co-immunoprecipitation, mutational analysis (C-terminal double point mutant) Biochemical and biophysical research communications Medium 39522233

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Histone deacetylases and SAP18, a novel polypeptide, are components of a human Sin3 complex. Cell 506 9150135
2002 Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex. Proceedings of the National Academy of Sciences of the United States of America 180 11960000
2004 The negative regulator of Gli, Suppressor of fused (Sufu), interacts with SAP18, Galectin3 and other nuclear proteins. The Biochemical journal 93 14611647
2000 The GAGA factor of Drosophila interacts with SAP18, a Sin3-associated polypeptide. EMBO reports 54 11256608
2009 Recruitment of a SAP18-HDAC1 complex into HIV-1 virions and its requirement for viral replication. PLoS pathogens 52 19503603
2019 CXCR2 expression on granulocyte and macrophage progenitors under tumor conditions contributes to mo-MDSC generation via SAP18/ERK/STAT3. Cell death & disease 51 31395859
2010 Human SAP18 mediates assembly of a splicing regulatory multiprotein complex via its ubiquitin-like fold. RNA (New York, N.Y.) 42 20966198
2019 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. Cell death and differentiation 40 30670829
2001 Drosophila SAP18, a member of the Sin3/Rpd3 histone deacetylase complex, interacts with Bicoid and inhibits its activity. Development genes and evolution 30 11455422
2005 Sap18 is required for the maternal gene bicoid to direct anterior patterning in Drosophila melanogaster. Developmental biology 24 15649476
1998 Cloning of the murine transcriptional corepressor component SAP18 and differential expression of its mRNA in the hematopoietic hierarchy. Gene 19 9511770
2002 The second largest subunit of mouse DNA polymerase epsilon, DPE2, interacts with SAP18 and recruits the Sin3 co-repressor protein to DNA. Journal of biochemistry 16 11872158
2006 Structure of SAP18: a ubiquitin fold in histone deacetylase complex assembly. Biochemistry 14 17002296
2020 A C21-steroidal derivative suppresses T-cell lymphoma in mice by inhibiting SIRT3 via SAP18-SIN3. Communications biology 12 33273692
2023 Functional role of SAP18 protein: From transcriptional repression to splicing regulation. Cell biochemistry and function 10 37486712
2010 Drosophila melanogaster SAP18 protein is required for environmental stress responses. FEBS letters 10 21146528
2008 SAP18 promotes Krüppel-dependent transcriptional repression by enhancer-specific histone deacetylation. The Journal of biological chemistry 8 19049982
2007 Chick Hairy1 protein interacts with Sap18, a component of the Sin3/HDAC transcriptional repressor complex. BMC developmental biology 6 17623094
2024 Nsp10-interacting host protein SAP18 restricts PEDV replication in Marc-145 cells via enhancing dephosphorylation of RIG-I. Veterinary microbiology 3 38795403
2019 Correction: CXCR2 expression on granulocyte and macrophage progenitors under tumor conditions contributes to mo-MDSC generation via SAP18/ERK/STAT3. Cell death & disease 3 31488810
2024 BioID proximity mapping reveals novel SAP18 interactions in the prespliceosomal complex. Biochemical and biophysical research communications 2 39522233
2025 Plant responses to full moonlight requires the SUVH4 HMTase which may target active genes via interaction with the splicing factor SAP18. Plant science : an international journal of experimental plant biology 1 41109507

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