Affinage

SP140

Nuclear body protein SP140 · UniProt Q13342

Length
867 aa
Mass
98.2 kDa
Annotated
2026-06-10
23 papers in source corpus 16 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SP140 is an immune-restricted, nuclear body-localized epigenetic reader that acts as a transcriptional co-repressor enforcing macrophage and hematopoietic cell identity by silencing lineage-inappropriate genes (PMID:28783698). It preferentially occupies promoters bearing H3K27me3 (e.g., the HOXA cluster) in macrophages and ensures their repression, and its loss severely compromises microbe-induced macrophage activation (PMID:28783698). Repression is executed through recruitment of the PRC2 and NuRD complexes, directing H3K27me3 deposition and NuRD binding at target loci (PMID:39718989), and through restraint of topoisomerase TOP1/TOP2 activity to maintain heterochromatin; loss of SP140 unleashes topoisomerase activity, de-represses silenced genes, and impairs bacterial killing, defects rescued by pharmacological TOP1/2 inhibition (PMID:35952671). SP140 also gatekeeps the endothelial-to-hematopoietic transition through TOP1-dependent chromatin remodeling (PMID:41397285). As a negative regulator of innate immunity, SP140 restrains type I interferon: it represses Ifnb1 not directly but by repressing RESIST, a stabilizer of Ifnb1 mRNA that counteracts TTP/CCR4-NOT-mediated destabilization (PMID:40500448), and Sp140-deficient mice are susceptible to Legionella and Mycobacterium tuberculosis in an IFNAR-dependent manner (PMID:34151776). SP140 loss in hematopoietic cells drives Proteobacteria blooms, altered antimicrobial programs, and transmissible colitis (PMID:36130593). The protein is regulated post-translationally: its atypical PHD finger does not bind histone H3 but is recognized by the prolyl isomerase Pin1, which isomerizes a phosphorylated pThr-Pro bond in the PHD L3 loop (PMID:24267382), and the PHD finger also binds Ubc9/SUMO-1 and acts as an intramolecular SUMO E3 ligase for the adjacent multi-SUMOylated bromodomain (PMID:30465816). These activities link SP140 genetically and functionally to intestinal inflammation, Crohn's disease, and lymphoma biology (PMID:36130593, PMID:39718989).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2002 Low

    Established SP140 as a nuclear body protein with a possible innate antiviral role, the first functional context for the gene.

    Evidence Yeast two-hybrid screen for HIV-1 Vif partners plus immunofluorescence colocalization in non-permissive cell lines

    PMID:12368356

    Open questions at the time
    • Vif interaction consequence never functionally validated
    • no direct antiviral mechanism defined
    • single low-confidence approach
  2. 2009 Low

    Confirmed SP140 as a constituent of PML nuclear bodies, defining its subcellular compartment.

    Evidence Indirect immunofluorescence and clinical serology in PBC patients using Sp140-expressing neuroblastoma cells

    PMID:19861957

    Open questions at the time
    • no functional consequence of NB localization tested
    • localization only by single approach
  3. 2013 High

    Determined that the SP140 PHD finger is an atypical non-histone-binding fold regulated by Pin1, revealing post-translational control of the reader.

    Evidence NMR solution structure, in vitro phosphopeptide binding, and co-IP of FLAG-Sp140 with endogenous Pin1

    PMID:24267382

    Open questions at the time
    • functional outcome of Pin1-catalyzed isomerization on SP140 activity not defined
    • kinase generating the phospho-Thr unknown
  4. 2017 High

    Defined SP140 as a chromatin reader occupying H3K27me3-marked silenced promoters to maintain macrophage identity, establishing its core transcriptional repressor role.

    Evidence ChIP-seq chromatin occupancy plus SP140 knockdown and macrophage activation assays in mouse and human cells

    PMID:28783698

    Open questions at the time
    • effector complexes mediating repression not yet identified at this stage
    • mechanism of H3K27me3-locus targeting unresolved
  5. 2018 High

    Showed SP140 is itself SUMO-regulated and that its PHD finger is an intramolecular SUMO E3 ligase, adding a layer of self-modification control.

    Evidence Mass spectrometry SUMO-site mapping, NMR binding to Ubc9/SUMO-1, and in vitro SUMOylation reconstitution

    PMID:30465816

    Open questions at the time
    • functional consequence of bromodomain SUMOylation on chromatin activity not established in cells
    • regulation of SUMOylation in vivo unknown
  6. 2018 Medium

    Extended SP140's repressor role to NF-κB-driven inflammatory transcription in B cells.

    Evidence siRNA knockdown with RNA-seq and NF-κB luciferase reporter assays in lymphoblastoid lines

    PMID:30102396

    Open questions at the time
    • direct vs indirect repression of NF-κB targets not distinguished
    • single cell-type context
  7. 2021 High

    Placed SP140 as a negative regulator of type I IFN whose loss causes IFNAR-dependent susceptibility to intracellular bacteria, linking the gene to infection outcome.

    Evidence Sp140-/- mice in Legionella and M. tuberculosis models with genetic Ifnar-/- epistasis rescue

    PMID:34151776

    Open questions at the time
    • molecular mechanism of IFN repression not yet defined at this stage
    • did not distinguish transcriptional vs post-transcriptional control
  8. 2021 Medium

    Identified a role for SP140 in IgE-dependent mast cell activation, broadening its immune-cell functions.

    Evidence siRNA knockdown in bone marrow-derived mast cells with histamine release and cytokine assays

    PMID:34156030

    Open questions at the time
    • no mechanistic pathway placement
    • single lab, single readout
  9. 2022 High

    Revealed that SP140 represses topoisomerases TOP1/TOP2 to maintain heterochromatin and macrophage fate, providing a mechanistic basis for gene silencing.

    Evidence Proteomic interactor identification, Sp140-/- mice, and pharmacological TOP1/2 inhibitor rescue in vivo and in vitro

    PMID:35952671

    Open questions at the time
    • biochemical mode of topoisomerase inhibition not detailed
    • link between topoisomerase restraint and specific H3K27me3 loci incomplete
  10. 2022 High

    Connected SP140 loss to gut dysbiosis and transmissible colitis, tying the molecular phenotype to intestinal inflammatory disease.

    Evidence Hematopoietic-specific Sp140-/- mice, cohousing/antibiotic experiments, microbiome sequencing, and human patient phagocyte analysis

    PMID:36130593

    Open questions at the time
    • causal microbial species not pinned to a single mechanism
    • phagocyte program defects not fully resolved at the molecular level
  11. 2022 Medium

    Showed SP140 directly represses STAT1 transcription, with overexpression driving a proinflammatory macrophage phenotype.

    Evidence ChIP, ATAC-seq, and SP140 overexpression/knockdown in macrophages with cytokine ELISAs

    PMID:36600652

    Open questions at the time
    • direct STAT1 promoter occupancy effect on downstream signaling not fully traced
    • single lab
  12. 2022 Medium

    Provided a selective small-molecule tool (GSK761) demonstrating SP140 chromatin binding is druggable and reprograms inflammatory macrophages.

    Evidence GSK761 inhibitor with ChIP-seq, LPS stimulation, and flow cytometry in macrophages

    PMID:35986286

    Open questions at the time
    • on-target specificity beyond reported readouts not exhaustively defined
    • single lab
  13. 2024 Medium

    Showed SP140 tumor expression can be driven by an LTR8B ERV-derived intronic promoter under MAPK control, affecting interferon sensitivity.

    Evidence Transcriptomics, ERV promoter silencing, and interferon cytotoxicity assays in fibrosarcoma cells

    PMID:38751339

    Open questions at the time
    • generality across tumor types unknown
    • link between ERV-driven isoform and canonical repressor function unclear
  14. 2025 High

    Resolved the mechanism of IFN regulation: SP140 represses RESIST, an Ifnb1 mRNA stabilizer, rather than repressing Ifnb1 transcription directly, defining a post-transcriptional axis.

    Evidence Sp140-/- genetic epistasis, RESIST target identification, mRNA stability assays, and rescue experiments

    PMID:40500448

    Open questions at the time
    • direct chromatin mechanism of RESIST repression not fully detailed
    • RESIST molecular function on Ifnb1 mRNA not structurally resolved
  15. 2025 Medium

    Demonstrated SP140 inhibits gammaherpesvirus MHV68 independently of its Ifnb1 mRNA regulatory function, establishing separable antiviral and IFN functions.

    Evidence Sp140-/- mouse MHV68 infection with epistasis against Ifnb1 regulation

    PMID:40500448

    Open questions at the time
    • antiviral effector mechanism not defined
    • single lab
  16. 2025 High

    Identified PRC2 and NuRD as the effector complexes SP140 recruits to deposit H3K27me3 and silence growth/leukemia loci, completing the repression mechanism.

    Evidence Interactomics, ChIP-seq, and multi-omics in Burkitt lymphoma cells

    PMID:39718989

    Open questions at the time
    • recruitment determinants and locus selectivity not fully mapped
    • relationship to topoisomerase repression not integrated
  17. 2026 Medium

    Showed SP140 gatekeeps the endothelial-to-hematopoietic transition via TOP1-dependent chromatin remodeling, extending its repressor role to HSC specification.

    Evidence CRISPR screen, transient SP140 KO/GSK761, CUT&TAG, TOP1-inhibitor epistasis, and transplantation in immunodeficient mice

    PMID:41397285

    Open questions at the time
    • durability and therapeutic window of transient inhibition unresolved
    • single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SP140 integrates topoisomerase restraint, PRC2/NuRD recruitment, and SUMO/Pin1 self-regulation into locus-specific targeting, and whether one effector axis predominates in each disease context, remains unresolved.
  • no unified model linking topoisomerase repression to H3K27me3 deposition
  • how SUMOylation and Pin1 isomerization tune chromatin activity in vivo is unknown
  • determinants of SP140 locus selectivity unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 2 GO:0098772 molecular function regulator activity 2 GO:0016740 transferase activity 1 GO:0042393 histone binding 1
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-4839726 Chromatin organization 3 R-HSA-1266738 Developmental Biology 1
Partners
EZH2PIN1SP140UBC9
Complex memberships
PML nuclear body

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2025 SP140 does not directly repress Ifnb1 transcription; instead, SP140 negatively regulates Ifnb1 mRNA stability by directly repressing expression of a previously uncharacterized regulator called RESIST (annexin 2 receptor). RESIST promotes Ifnb1 mRNA stability by counteracting destabilization mediated by the tristetraprolin (TTP) family of RNA-binding proteins and the CCR4-NOT deadenylase complex. Genetic epistasis (Sp140-/- mice), identification of RESIST as SP140 target gene, mRNA stability assays, functional rescue experiments Nature High 40500448
2025 SP140 localizes within nuclear bodies and inhibits replication of the gammaherpesvirus MHV68 through a mechanism independent of its ability to regulate Ifnb1 mRNA levels, establishing dual antiviral and interferon regulatory functions. Sp140-/- mouse infections with MHV68, epistasis with Ifnb1 regulation Nature Medium 40500448
2021 SP140 represses type I IFN transcription during bacterial infection, acting as a negative regulator of type I IFNs. Sp140-/- mice are susceptible to Legionella pneumophila and Mycobacterium tuberculosis infection, and this susceptibility is rescued by genetic deletion of the type I IFN receptor (Ifnar-/-). Sp140-/- mouse generation, bacterial infection models, genetic epistasis cross to Ifnar-/- mice eLife High 34151776
2017 SP140 preferentially occupies promoters of silenced, lineage-inappropriate genes bearing the histone modification H3K27me3 (e.g., HOXA cluster) in human macrophages and ensures their repression. Depletion of SP140 in macrophages results in severely compromised microbe-induced activation. ChIP-seq/chromatin occupancy analysis, SP140 knockdown in mouse and human macrophages, functional macrophage activation assays Science immunology High 28783698
2022 SP140 acts as a repressor of topoisomerases (TOP1 and TOP2), maintaining heterochromatin and macrophage fate. Loss of SP140 results in unleashed topoisomerase activity, de-repression of developmentally silenced genes, and defective microbe-inducible macrophage transcriptional programs and bacterial killing. Pharmacological inhibition of TOP1/2 rescues these defects in Sp140-/- mice. Global proteomic strategy to identify SP140 interactors, Sp140-/- mice, pharmacological TOP1/2 inhibitor rescue experiments in vivo and in vitro Cell High 35952671
2022 SP140 negatively regulates STAT1 transcription by directly binding to the STAT1 promoter (shown by chromatin immunoprecipitation), and SP140 overexpression in macrophages induces a proinflammatory phenotype with increased IFN-γ production. ChIP, ATAC-seq, SP140 overexpression and knockdown in macrophages and tumor-associated macrophages, cytokine ELISAs Journal for immunotherapy of cancer Medium 36600652
2022 Loss of SP140 in hematopoietic cells leads to blooms of Proteobacteria (Helicobacter in mice; Enterobacteriaceae in humans with SP140 loss-of-function variant), and phagocytes from Sp140-/- mice or patients show altered antimicrobial defense programs; colitis driven by altered microbiota is transmissible by cohousing and ameliorated with antibiotics. Sp140-/- mouse model (hematopoietic-specific), cohousing and antibiotic experiments, microbiome sequencing, phagocytic function assays Cell host & microbe High 36130593
2013 The PHD finger of Sp140 adopts an atypical fold that does not bind histone H3 tails but is recognized by the peptidylprolyl isomerase Pin1. Pin1 specifically binds a phosphopeptide corresponding to the L3 loop of Sp140-PHD and catalyzes cis-trans isomerization of a pThr-Pro bond. Co-immunoprecipitation confirmed FLAG-Sp140 interaction with endogenous Pin1 in vivo. NMR solution structure, in vitro binding assays, co-immunoprecipitation (FLAG-Sp140 with endogenous Pin1) The FEBS journal High 24267382
2018 Sp140 is a multi-SUMO-1 target with at least 13 SUMOylation sites including the bromodomain. The PHD finger directly binds the SUMO E2 ligase Ubc9 and SUMO-1 (by NMR), and acts as a SUMO E3 ligase promoting intramolecular SUMOylation of the adjacent bromodomain in vitro. Mass spectrometry identification of SUMOylation sites, NMR binding experiments, in vitro SUMOylation reactions, biochemical experiments in Burkitt's lymphoma cells and HEK293T cells Biochimica et biophysica acta. General subjects High 30465816
2018 SP140 silencing in lymphoblastoid cell lines leads to upregulation of NF-κB transcriptional activity and NF-κB-driven inflammatory genes, including those involved in cytokine production and cell-cell adhesion, identifying SP140 as a repressor of NF-κB-driven transcription in B cells. SP140 siRNA knockdown, RNA-seq, luciferase NF-κB reporter assay, promoter enrichment analysis Human molecular genetics Medium 30102396
2025 SP140 represses specific loci by recruiting the Polycomb Repressive Complex 2 (PRC2) and NuRD complex. SP140 interaction with PRC2 and NuRD is functional, directing H3K27me3 deposition and NuRD binding at target genes implicated in cellular growth and leukemia progression. Interactomics (proteomics), ChIP-seq, multi-omics in Burkitt lymphoma cell lines Nucleic acids research High 39718989
2002 Sp140, identified by yeast two-hybrid screen as a potential HIV-1 Vif binding partner, is found specifically in all non-permissive (NP) cells tested, and HIV-1 infection induces partial dispersal of Sp140 from nuclear bodies into cytosolic colocalization with Vif, implicating Sp140 in an innate antiviral response. Yeast two-hybrid screen, indirect immunofluorescence colocalization, cell line panel comparison Journal of virology Low 12368356
2009 Sp140 is a component of PML nuclear bodies (NBs). Anti-Sp140 antibodies in PBC patients were identified using a neuroblastoma cell line expressing Sp140, confirming its nuclear body localization and identifying the NB as a multiantigenic complex. Indirect immunofluorescence, neuroblastoma cell line expressing Sp140, clinical serology in PBC patients The American journal of gastroenterology Low 19861957
2022 SP140 inhibition by small molecule GSK761 reduces SP140 chromatin binding at transcriptional start sites of pro-inflammatory cytokine/chemokine genes in inflammatory macrophages, reducing LPS-induced cytokine expression and monocyte-to-inflammatory macrophage differentiation, while inducing CD206+ regulatory macrophages. Small molecule SP140 inhibitor (GSK761) development, ChIP-seq in inflammatory macrophages, LPS stimulation assays, flow cytometry BMC biology Medium 35986286
2024 SP140 expression in tumors can be driven by an alternative intronic promoter derived from an intronic endogenous retrovirus (LTR8B family), regulated by oncogenic MAPK signaling. Silencing this ERV promoter in a fibrosarcoma cell line increased sensitivity to interferon-mediated cytotoxicity and dysregulated multiple immune genes. Transcriptomic analysis, ERV promoter silencing (CRISPR or siRNA), interferon cytotoxicity assays Human molecular genetics Medium 38751339
2021 siRNA-mediated knockdown of Sp140 in bone marrow-derived cultured mast cells (BMCMCs) decreased IgE-dependent histamine release and cytokine production, establishing a role for Sp140 in IgE-dependent mast cell activation. siRNA knockdown in BMCMCs, IgE-dependent activation assays (histamine release, cytokine ELISA) JCI insight Medium 34156030
2026 SP140 acts as an epigenetic gatekeeper suppressing hematopoiesis. Transient SP140 inhibition unlocks transcription at endothelial-to-hematopoietic transition (EHT) loci through topoisomerase 1-dependent chromatin remodeling, and this effect is blocked by topoisomerase 1 inhibition. SP140 binding at EHT and HSC-specification gene loci was confirmed by CUT&TAG profiling. CRISPR/Cas9 screen, transient SP140 KO or GSK761 pharmacological inhibition, CUT&TAG chromatin profiling, topoisomerase 1 inhibitor epistasis, transplantation assays in immunodeficient mice Blood Medium 41397285

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons. eLife 79 34151776
2009 PML nuclear body component Sp140 is a novel autoantigen in primary biliary cirrhosis. The American journal of gastroenterology 68 19861957
2017 Maintenance of macrophage transcriptional programs and intestinal homeostasis by epigenetic reader SP140. Science immunology 62 28783698
2002 Implication of the lymphocyte-specific nuclear body protein Sp140 in an innate response to human immunodeficiency virus type 1. Journal of virology 54 12368356
2016 Whole Genome DNA Methylation Analysis of Obstructive Sleep Apnea: IL1R2, NPR2, AR, SP140 Methylation and Clinical Phenotype. Sleep 43 26888452
2022 Epigenetic reader SP140 loss of function drives Crohn's disease due to uncontrolled macrophage topoisomerases. Cell 30 35952671
2016 Highly Efficient Delivery of Functional Cargoes by a Novel Cell-Penetrating Peptide Derived from SP140-Like Protein. Bioconjugate chemistry 28 27070736
2018 SP140 regulates the expression of immune-related genes associated with multiple sclerosis and other autoimmune diseases by NF-κB inhibition. Human molecular genetics 26 30102396
2022 SP140 inhibits STAT1 signaling, induces IFN-γ in tumor-associated macrophages, and is a predictive biomarker of immunotherapy response. Journal for immunotherapy of cancer 24 36600652
2022 Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140. BMC biology 21 35986286
2025 SP140-RESIST pathway regulates interferon mRNA stability and antiviral immunity. Nature 15 40500448
2022 Immune chromatin reader SP140 regulates microbiota and risk for inflammatory bowel disease. Cell host & microbe 15 36130593
2013 Structure of human Sp140 PHD finger: an atypical fold interacting with Pin1. The FEBS journal 15 24267382
2021 The role of Sp140 revealed in IgE and mast cell responses in Collaborative Cross mice. JCI insight 11 34156030
2018 Sp140 is a multi-SUMO-1 target and its PHD finger promotes SUMOylation of the adjacent Bromodomain. Biochimica et biophysica acta. General subjects 11 30465816
2024 SP140 inhibitor suppressing TRIM22 expression regulates glioma progress through PI3K/AKT signaling pathway. Brain and behavior 8 38468469
2024 Transcriptional regulators SP110 and SP140 modulate inflammatory response genes in Mycobacterium tuberculosis-infected human macrophages. Microbiology spectrum 5 39162523
2025 The SP140-RESIST pathway regulates interferon mRNA stability and antiviral immunity. bioRxiv : the preprint server for biology 4 39974928
2024 An endogenous retrovirus regulates tumor-specific expression of the immune transcriptional regulator SP140. Human molecular genetics 3 38751339
2025 SP140 represses specific loci by recruiting polycomb repressive complex 2 and NuRD complex. Nucleic acids research 2 39718989
2023 The Epigenetic Reader Protein SP140 Regulates Dendritic Cell Activation, Maturation and Tolerogenic Potential. Current issues in molecular biology 2 37232738
2026 Transient SP140 inhibition unlocks hematopoietic stem cell fate from human pluripotent stem cells. Blood 1 41397285
2025 SP140 limits type I interferon-driven pathology, preserving T cell motility and promoting resistance in tuberculosis. bioRxiv : the preprint server for biology 0 41415425

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