{"gene":"SP110","run_date":"2026-06-10T07:46:38","timeline":{"discoveries":[{"year":2000,"finding":"SP110 localizes to PML-Sp100 nuclear bodies in ATRA-treated NB4 cells, and an SP110 DNA-binding domain fusion protein activates transcription of a reporter gene in transfected mammalian cells. SP110 also markedly increases ATRA-mediated expression of a reporter gene containing a retinoic acid response element, indicating SP110 functions as a nuclear hormone receptor transcriptional coactivator.","method":"Immunofluorescence localization, transfection-based luciferase/reporter assay, ATRA treatment of NB4 cells","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunofluorescence tied to functional consequence, reporter assay in mammalian cells; single lab with two orthogonal methods","pmids":["10913195"],"is_preprint":false},{"year":2006,"finding":"Loss-of-function mutations in SP110 (truncating and other mutations) cause veno-occlusive disease with immunodeficiency (VODI), characterized by severe hypogammaglobulinemia, combined T and B cell immunodeficiency, absent germinal centers, absent plasma cells, and hepatic veno-occlusive disease, establishing SP110 as required for normal immune development.","method":"Human genetics/Sanger sequencing of SP110 in VODI patients; clinical and immunological phenotyping","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple independent truncating mutations in SP110 segregating with disease phenotype, replicated in multiple families; human genetics with clear molecular and cellular phenotype","pmids":["16648851"],"is_preprint":false},{"year":2012,"finding":"SP110 deficiency in human B cells compromises their ability to respond to T cell-dependent stimuli (CD40L, IL-21) and differentiate into immunoglobulin-secreting plasma cells in vitro, as demonstrated using cells from VODI patients with SP110 mutations. Analysis of 4 new alleles confirmed VODI is caused by reduced functional SP110 protein levels. Mutant SP110 proteins are subject to enhanced proteasomal degradation.","method":"Immunofluorescence of transfected mutant proteins in HEp-2 cells; flow cytometry B-cell phenotyping; B-cell stimulation assays; gene expression arrays","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (protein localization, B-cell functional assay, gene expression profiling) in a single rigorous study; confirmed reduced SP110 protein as the mechanistic basis","pmids":["22621957"],"is_preprint":false},{"year":2017,"finding":"SP110 is SUMO1-modified and resides in PML nuclear bodies in a SUMOylated state. During HBV infection, HBx protein interacts with SP110 and drives deSUMOylation-dependent release of SP110 from PML-NBs. SP110 knockdown reduces viral DNA load by activating the type I interferon response pathway. SP110 regulates HBx direct target genes, and the SP110-HBx interaction is required for HBx recruitment to the promoters of co-regulated genes, where HBx modulates recruitment of p300/HDAC1 to alter host gene expression in favor of viral persistence.","method":"Co-immunoprecipitation (SP110-HBx interaction), immunofluorescence (SP110 localization), SUMO1 modification assay, SP110 knockdown with viral load quantification, ChIP (HBx and p300/HDAC1 promoter recruitment)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP for HBx interaction, direct localization with functional consequence (SUMO-dependent PML-NB exit), ChIP for promoter recruitment, KD with defined phenotype; single lab with multiple orthogonal methods","pmids":["29046350"],"is_preprint":false},{"year":2017,"finding":"SP110 interacts with HSP5 (Hspa5/BiP) to activate endoplasmic reticulum (ER) stress-induced apoptosis in mouse macrophages, which is essential for Sp110-enhanced resistance to M. tuberculosis. SP110 also interacts with RNA-binding protein Ncl (nucleolin) and promotes its degradation, thereby downregulating Bcl2 (normally stabilized by Ncl). Additionally, SP110 promotes degradation of ribosomal protein Rps3a, upregulating pro-apoptotic PARP activity. Inhibition of the ER stress pathway abolished SP110-enhanced macrophage apoptosis and increased intracellular Mtb survival.","method":"Proteomics/MS (253 interacting proteins identified), Co-immunoprecipitation, ER stress pathway inhibition, macrophage overexpression, Mtb survival assay, transgenic cattle macrophages","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based interactome with functional follow-up (ER stress inhibition, KO/overexpression phenotype); single lab with multiple methods but functional mechanism validated in transgenic cattle macrophages","pmids":["28969051"],"is_preprint":false},{"year":2018,"finding":"The N-terminal fragment (amino acids 1–276) of SP110 interacts with p50 (an NF-κB subunit) in the cytoplasm, and this interaction is required for downregulation of p50-driven TNF-α promoter activity. Different SP110 isoforms have distinct effects on NF-κB-mediated transcription. The middle region of SP110 contains a nucleolar localization signal (NoLS) with monopartite and bipartite NLS elements that directs SP110 to the nucleolus under certain conditions, whereas the middle and C-terminal regions also govern localization to other cellular compartments.","method":"Luciferase reporter assay (deletion mutants), co-immunoprecipitation, confocal microscopy (GFP-tagged SP110 mutants), Western blotting","journal":"Journal of biomedical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deletion mutagenesis combined with reporter assay and Co-IP identifies functional domains; confocal microscopy for localization; single lab with multiple orthogonal methods","pmids":["29642903"],"is_preprint":false},{"year":2024,"finding":"UBR7 E3 ubiquitin ligase ubiquitinates SP110 at critical residues within its SAND domain. This ubiquitination of SP110 downregulates genes in the type I interferon response pathway. Wild-type but not ubiquitination-defective mutant SP110 is recruited to type I interferon response pathway gene promoters. Silencing UBR7 induces IRF7 phosphorylation and augments IFN-β and downstream ISGs, confirming that UBR7-mediated SP110 ubiquitination suppresses IFN-β immune signaling during HBV infection.","method":"In vitro ubiquitination assay, RNA-seq (UBR7/SP110 knockdown), Co-IP (UBR7-SP110 interaction), site-directed mutagenesis (ubiquitination-defective SP110), ChIP (SP110 promoter recruitment), scRNA-seq patient data analysis","journal":"ACS infectious diseases","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro ubiquitination assay with mutagenesis of SAND domain residues, ChIP for promoter recruitment of wild-type vs mutant SP110, KD phenotype with multiple orthogonal methods; single lab","pmids":["38938101"],"is_preprint":false},{"year":2024,"finding":"In M. tuberculosis-infected THP-1 macrophages, depletion of SP110 (and/or SP140) impairs induction of inflammatory response genes including type I IFN response genes, while genes related to phosphorylation are upregulated upon SP110/SP140 knockdown. This establishes human SP110 as a positive transcriptional regulator of inflammatory/IFN response genes during Mtb infection.","method":"Genome-wide transcriptional profiling, RT-qPCR, ELISA, siRNA knockdown of SP110 and/or SP140 in THP-1 macrophages infected with M. tuberculosis","journal":"Microbiology spectrum","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide transcriptomics plus orthogonal RT-qPCR and ELISA validation; single lab but multiple methods","pmids":["39162523"],"is_preprint":false},{"year":2016,"finding":"SP110 regulates transcription of macrophage genes involved in immune responses, apoptosis, defense, and inflammatory responses upon Mtb infection. SP110 upregulates the pro-apoptotic factor Bmf by inhibiting miR-125a, and forced Bmf expression induces macrophage apoptosis, placing SP110 upstream of a miRNA-Bmf-apoptosis axis.","method":"Integrated transcriptome analysis, miRNA expression profiling, Bmf overexpression/knockdown, apoptosis assay in RAW264.7 macrophages","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptome plus mechanistic follow-up (miR-125a inhibition, Bmf forced expression with apoptosis readout); single lab with two orthogonal approaches","pmids":["26912204"],"is_preprint":false},{"year":2026,"finding":"SP110 is a potent inhibitor of type I interferon-driven cell death that counteracts a toxic activity of SP100. Loss of SP110 leads to mitotic retention of SP100 and PML nuclear bodies, which associate with segregating chromosomes, causing micronucleus formation, DNA damage, and genotoxic cell death. Cryo-EM and AlphaFold modelling combined with cellular biochemistry demonstrate that SP110 dissolves toxic SP100 oligomers via direct interactions between their CARD (caspase activation and recruitment) domains, establishing a structural mechanism for PML body disassembly during mitosis.","method":"Genome-wide CRISPR-Cas9 genetic screen (triphosphorylated RNA stimulation), cryo-electron microscopy, AlphaFold structural modelling, cellular biochemistry (Co-IP, domain mapping), live-cell imaging (mitotic SP100/PML retention), micronucleus assay, DNA damage assay","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus AlphaFold plus cellular biochemistry plus genetic screen with defined cell death phenotype; multiple orthogonal methods in a single rigorous study","pmids":["41826696"],"is_preprint":false},{"year":2007,"finding":"SP110 expression is induced by Anaplasma phagocytophilum infection of human HL-60 promyelocytic cells, and siRNA-mediated knockdown of SP110 reduces A. phagocytophilum infection and multiplication, demonstrating that SP110 is required for this intracellular pathogen to establish infection.","method":"Real-time RT-PCR, RNA interference (siRNA knockdown), quantitative PCR of bacterial load","journal":"BMC infectious diseases","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (RNAi + qPCR); no mechanistic pathway placement beyond requirement for infection","pmids":["17883869"],"is_preprint":false},{"year":2015,"finding":"Transgenic cattle with SP110 knocked into their genome via TALE nickase-mediated homologous recombination control growth and multiplication of Mycobacterium bovis, shift cell death from necrosis to apoptosis upon infection, and resist low-dose M. bovis transmission in vivo, demonstrating that SP110 expression promotes the apoptotic pathway and confers tuberculosis resistance at the organismal level.","method":"TALEN-mediated genome knockin (homologous recombination), in vitro and in vivo M. bovis challenge, apoptosis/necrosis pathway analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined genetic knockin with in vivo challenge and mechanistic pathway determination (apoptosis vs necrosis); single study with multiple readouts","pmids":["25733846"],"is_preprint":false},{"year":2025,"finding":"Species-specific alternative splicing of the bovine SP110 gene produces a truncated bSP110c variant that lacks the SAND domain required for anti-tuberculosis function. This truncated isoform predominates in dairy cattle due to a ruminant-specific absence of a pre-SAND exon, which promotes bSP110c splicing. Substituting the pre-SAND region with human or equine sequences suppresses bSP110c and increases bSP110a/b expression, while bSP110c shows significantly reduced resistance to M. bovis compared to bSP110a and bSP110b.","method":"RT-PCR splice variant characterization, minigene splicing assay, M. bovis infection assay comparing isoforms, domain deletion analysis (SAND domain), sequence substitution experiments","journal":"Veterinary research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional comparison of splice variants in infection assay plus mechanistic minigene splicing experiments; single lab with multiple orthogonal methods","pmids":["41382217"],"is_preprint":false}],"current_model":"SP110 is an interferon-inducible, leukocyte-enriched nuclear body protein that resides in PML-SP100 nuclear bodies in a SUMO1-modified state, functions as a transcriptional coactivator/regulator (including of NF-κB and type I IFN response genes) through its N-terminal domain interaction with p50 and its SAND domain, dissolves toxic SP100 oligomers via CARD-domain interactions to enable PML body disassembly during mitosis, promotes macrophage apoptosis over necrosis upon mycobacterial infection via ER stress (Hspa5 interaction), Bcl2 suppression (Ncl degradation), and PARP activation, and is subject to ubiquitination by UBR7 (at SAND domain residues) and to HBx-driven deSUMOylation that releases it from PML bodies to modulate host gene expression during HBV infection; loss-of-function mutations cause VODI primary immunodeficiency with impaired B-cell differentiation."},"narrative":{"mechanistic_narrative":"SP110 is an interferon-inducible nuclear body protein that acts as a transcriptional regulator within the PML-SP100 nuclear body system and as a key controller of innate immune and cell death programs during intracellular infection [PMID:10913195, PMID:41826696]. It localizes to PML-SP100 nuclear bodies and functions as a transcriptional coactivator, including of retinoic-acid-responsive promoters via its DNA-binding domain [PMID:10913195], and modulates NF-κB output through an N-terminal (aa 1–276) interaction with the p50 subunit that downregulates p50-driven TNF-α promoter activity, with distinct isoforms exerting distinct effects [PMID:29642903]. SP110 governs PML body dynamics by dissolving toxic SP100 oligomers through direct CARD-CARD domain interactions, enabling PML body disassembly during mitosis; loss of SP110 causes mitotic retention of SP100/PML on segregating chromosomes, micronucleus formation, DNA damage, and type I interferon-driven genotoxic cell death [PMID:41826696]. During mycobacterial infection SP110 reprograms macrophage death from necrosis toward apoptosis through ER stress activation via Hspa5/BiP, Bcl2 suppression through nucleolin degradation, PARP activation via Rps3a degradation, and a miR-125a–Bmf pro-apoptotic axis, and this activity confers tuberculosis resistance at the organismal level [PMID:28969051, PMID:26912204, PMID:25733846]. As a positive transcriptional regulator of inflammatory and type I IFN response genes, SP110 is recruited to IFN-pathway promoters, an activity opposed by UBR7-mediated ubiquitination at SAND-domain residues and exploited during HBV infection, where HBx drives deSUMOylation-dependent release of SP110 from PML bodies to remodel host gene expression [PMID:29046350, PMID:38938101, PMID:39162523]. Loss-of-function mutations that reduce functional SP110 protein cause veno-occlusive disease with immunodeficiency (VODI), with impaired B-cell differentiation into immunoglobulin-secreting plasma cells [PMID:16648851, PMID:22621957].","teleology":[{"year":2000,"claim":"Established SP110 as a PML-SP100 nuclear body resident with intrinsic transcriptional coactivator activity, framing it as a regulator of gene expression rather than a passive structural protein.","evidence":"Immunofluorescence localization in ATRA-treated NB4 cells plus reporter assays in transfected mammalian cells","pmids":["10913195"],"confidence":"Medium","gaps":["Direct endogenous target genes not identified","Mechanism of coactivation at native promoters undefined"]},{"year":2006,"claim":"Defined the physiological requirement for SP110 by linking loss-of-function mutations to VODI, demonstrating SP110 is essential for normal immune development.","evidence":"Sanger sequencing of SP110 in VODI families with clinical and immunological phenotyping","pmids":["16648851"],"confidence":"High","gaps":["Molecular pathway connecting SP110 loss to B-cell failure unresolved","Cause of hepatic veno-occlusive disease not mechanistically explained"]},{"year":2007,"claim":"Showed SP110 is induced by and required for an intracellular bacterial infection, implicating it in host-pathogen interactions.","evidence":"RT-PCR and siRNA knockdown with bacterial load quantification in HL-60 cells infected with Anaplasma phagocytophilum","pmids":["17883869"],"confidence":"Low","gaps":["Single method (RNAi + qPCR) without mechanistic pathway placement","No identification of how SP110 supports infection"]},{"year":2012,"claim":"Resolved the molecular basis of VODI as reduced functional SP110 protein and connected it to a defect in T-dependent B-cell differentiation into plasma cells.","evidence":"Mutant protein expression in HEp-2 cells, flow cytometry, B-cell stimulation assays, and gene expression arrays from VODI patients","pmids":["22621957"],"confidence":"High","gaps":["Specific transcriptional targets driving plasma cell differentiation not defined","Link between enhanced proteasomal degradation and B-cell phenotype not directly demonstrated"]},{"year":2015,"claim":"Demonstrated at the organismal level that SP110 shifts infected-cell death from necrosis to apoptosis and confers tuberculosis resistance.","evidence":"TALEN-mediated SP110 knockin transgenic cattle with in vitro/in vivo M. bovis challenge and apoptosis/necrosis analysis","pmids":["25733846"],"confidence":"Medium","gaps":["Molecular effectors of the apoptotic shift not identified in this study","Generalizability beyond bovine system not addressed"]},{"year":2016,"claim":"Placed SP110 upstream of a defined pro-apoptotic axis, showing it induces Bmf by inhibiting miR-125a to drive macrophage apoptosis during Mtb infection.","evidence":"Integrated transcriptome and miRNA profiling with Bmf manipulation and apoptosis assays in RAW264.7 macrophages","pmids":["26912204"],"confidence":"Medium","gaps":["Direct binding of SP110 to relevant promoters not shown","How SP110 represses miR-125a undefined"]},{"year":2017,"claim":"Identified the biochemical mechanisms by which SP110 enforces apoptosis over necrosis: ER stress via Hspa5, Bcl2 suppression through nucleolin degradation, and PARP activation via Rps3a degradation.","evidence":"MS interactome (253 proteins), Co-IP, ER stress inhibition, and Mtb survival assays in macrophages including transgenic cattle cells","pmids":["28969051"],"confidence":"Medium","gaps":["Mechanism by which SP110 promotes target degradation not defined","Direct vs indirect nature of some interactions from large MS set uncertain"]},{"year":2017,"claim":"Revealed SUMO-dependent control of SP110 PML-body residence and its exploitation by HBV, where HBx interaction releases SP110 to remodel host transcription and aid viral persistence.","evidence":"Reciprocal Co-IP, SUMO1 modification assay, knockdown with viral load, and ChIP for HBx and p300/HDAC1 promoter recruitment","pmids":["29046350"],"confidence":"High","gaps":["SUMO ligase/protease controlling SP110 modification not identified","Full set of co-regulated host genes incompletely mapped"]},{"year":2018,"claim":"Mapped functional domains of SP110, defining an N-terminal p50-interacting region that suppresses NF-κB target activity and a middle-region NoLS controlling subcellular distribution.","evidence":"Deletion-mutant luciferase reporters, Co-IP, and confocal microscopy of GFP-tagged SP110 variants","pmids":["29642903"],"confidence":"Medium","gaps":["Physiological conditions triggering nucleolar localization unclear","Isoform-specific transcriptional effects not linked to defined target genes"]},{"year":2024,"claim":"Established SP110 as a positive transcriptional regulator of inflammatory and type I IFN response genes in human macrophages during Mtb infection.","evidence":"Genome-wide transcriptomics with RT-qPCR and ELISA validation following SP110/SP140 siRNA knockdown in THP-1 macrophages","pmids":["39162523"],"confidence":"Medium","gaps":["Direct vs indirect promoter targets not distinguished from SP140 contribution","Mechanism of transcriptional activation not resolved"]},{"year":2024,"claim":"Defined a post-translational brake on SP110 transcriptional activity: UBR7 ubiquitinates SAND-domain residues to block SP110 recruitment to type I IFN gene promoters and suppress IFN-β signaling.","evidence":"In vitro ubiquitination assay with SAND-residue mutagenesis, Co-IP, RNA-seq, and ChIP of wild-type vs ubiquitination-defective SP110","pmids":["38938101"],"confidence":"High","gaps":["Conditions regulating UBR7-SP110 ubiquitination not defined","Structural impact of SAND ubiquitination on chromatin recruitment unknown"]},{"year":2026,"claim":"Provided a structural mechanism for SP110 in PML body biology, showing it dissolves toxic SP100 CARD oligomers to enable mitotic PML body disassembly and prevent genotoxic IFN-driven cell death.","evidence":"Genome-wide CRISPR screen, cryo-EM, AlphaFold modelling, domain-mapping biochemistry, live-cell imaging, and micronucleus/DNA-damage assays","pmids":["41826696"],"confidence":"High","gaps":["How CARD-CARD dissolution is regulated through the cell cycle not detailed","Connection to SP110's transcriptional roles not integrated"]},{"year":2025,"claim":"Showed isoform identity dictates SP110 anti-tuberculosis function, with a SAND-lacking bovine splice variant losing activity due to a ruminant-specific exon arrangement.","evidence":"RT-PCR splice variant characterization, minigene splicing assays, M. bovis infection comparison of isoforms, and sequence substitution experiments","pmids":["41382217"],"confidence":"Medium","gaps":["Relevance to human SP110 isoform regulation not established","Molecular role of the SAND domain in anti-Mtb activity not directly demonstrated here"]},{"year":null,"claim":"How SP110's transcriptional coactivator activity, PML-body structural role, and pro-apoptotic infection responses are mechanistically unified, and what governs the SUMO/ubiquitin switching of its localization and activity, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model linking nuclear body disassembly to transcriptional output","Upstream signals controlling SP110 SUMOylation/ubiquitination undefined","Direct genome-wide SP110 binding map absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,5,7]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,7,6]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,8,9,11]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,3]}],"complexes":["PML-SP100 nuclear body"],"partners":["SP100","HBX","NFKB1","HSPA5","NCL","UBR7","SP140"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HB58","full_name":"Sp110 nuclear body protein","aliases":["Interferon-induced protein 41/75","Speckled 110 kDa","Transcriptional coactivator Sp110"],"length_aa":689,"mass_kda":78.4,"function":"Transcription factor. May be a nuclear hormone receptor coactivator. Enhances transcription of genes with retinoic acid response elements (RARE)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9HB58/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SP110","classification":"Not Classified","n_dependent_lines":22,"n_total_lines":1208,"dependency_fraction":0.018211920529801324},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SP110","total_profiled":1310},"omim":[{"mim_id":"607948","title":"MYCOBACTERIUM TUBERCULOSIS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/607948"},{"mim_id":"604457","title":"NUCLEAR BODY PROTEIN SP110; SP110","url":"https://www.omim.org/entry/604457"},{"mim_id":"235550","title":"HEPATIC VENOOCCLUSIVE DISEASE WITH IMMUNODEFICIENCY; VODI","url":"https://www.omim.org/entry/235550"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SP110"},"hgnc":{"alias_symbol":[],"prev_symbol":["IFI41","IFI75"]},"alphafold":{"accession":"Q9HB58","domains":[{"cath_id":"3.10.390.10","chopping":"459-532","consensus_level":"medium","plddt":81.117,"start":459,"end":532},{"cath_id":"3.30.40.10","chopping":"534-584","consensus_level":"medium","plddt":76.7571,"start":534,"end":584},{"cath_id":"1.20.920.10","chopping":"590-676","consensus_level":"high","plddt":72.593,"start":590,"end":676},{"cath_id":"1.10.533","chopping":"7-113","consensus_level":"high","plddt":90.2833,"start":7,"end":113}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HB58","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HB58-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HB58-F1-predicted_aligned_error_v6.png","plddt_mean":58.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SP110","jax_strain_url":"https://www.jax.org/strain/search?query=SP110"},"sequence":{"accession":"Q9HB58","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HB58.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HB58/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HB58"}},"corpus_meta":[{"pmid":"10913195","id":"PMC_10913195","title":"Sp110 localizes to the PML-Sp100 nuclear body and may function as a nuclear hormone receptor transcriptional coactivator.","date":"2000","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10913195","citation_count":125,"is_preprint":false},{"pmid":"25733846","id":"PMC_25733846","title":"TALE nickase-mediated SP110 knockin endows cattle with increased resistance to tuberculosis.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25733846","citation_count":109,"is_preprint":false},{"pmid":"16803959","id":"PMC_16803959","title":"Variants in the SP110 gene are associated with genetic susceptibility to tuberculosis in West Africa.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16803959","citation_count":83,"is_preprint":false},{"pmid":"16648851","id":"PMC_16648851","title":"Mutations in the gene encoding the PML nuclear body protein Sp110 are associated with immunodeficiency and hepatic veno-occlusive disease.","date":"2006","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16648851","citation_count":66,"is_preprint":false},{"pmid":"16816019","id":"PMC_16816019","title":"No associations of human pulmonary tuberculosis with Sp110 variants.","date":"2006","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16816019","citation_count":47,"is_preprint":false},{"pmid":"21222611","id":"PMC_21222611","title":"Identification of proteins interacting with human SP110 during the process of viral infections.","date":"2011","source":"Medicinal chemistry (Shariqah (United Arab Emirates))","url":"https://pubmed.ncbi.nlm.nih.gov/21222611","citation_count":42,"is_preprint":false},{"pmid":"23129390","id":"PMC_23129390","title":"Identification of genetic associations of SP110/MYBBP1A/RELA with pulmonary tuberculosis in the Chinese Han population.","date":"2012","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23129390","citation_count":39,"is_preprint":false},{"pmid":"22621957","id":"PMC_22621957","title":"Clinical, molecular, and cellular immunologic findings in patients with SP110-associated veno-occlusive disease with immunodeficiency syndrome.","date":"2012","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22621957","citation_count":35,"is_preprint":false},{"pmid":"29046350","id":"PMC_29046350","title":"Host transcription factor Speckled 110 kDa (Sp110), a nuclear body protein, is hijacked by hepatitis B virus protein X for viral persistence.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29046350","citation_count":33,"is_preprint":false},{"pmid":"27185954","id":"PMC_27185954","title":"Variants within the SP110 nuclear body protein modify risk of canine degenerative myelopathy.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/27185954","citation_count":31,"is_preprint":false},{"pmid":"17287948","id":"PMC_17287948","title":"SP110 polymorphisms are not associated with pulmonary tuberculosis in a South African population.","date":"2007","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17287948","citation_count":30,"is_preprint":false},{"pmid":"17149599","id":"PMC_17149599","title":"Resequencing and association analysis of the SP110 gene in adult pulmonary tuberculosis.","date":"2006","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17149599","citation_count":29,"is_preprint":false},{"pmid":"26912204","id":"PMC_26912204","title":"The Transcriptional Foundations of Sp110-mediated Macrophage (RAW264.7) Resistance to Mycobacterium tuberculosis H37Ra.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26912204","citation_count":26,"is_preprint":false},{"pmid":"21094769","id":"PMC_21094769","title":"SP110 as a novel susceptibility gene for Mycobacterium avium subspecies paratuberculosis infection in cattle.","date":"2010","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/21094769","citation_count":24,"is_preprint":false},{"pmid":"25006821","id":"PMC_25006821","title":"Polymorphisms of SP110 are associated with both pulmonary and extra-pulmonary tuberculosis among the Vietnamese.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25006821","citation_count":23,"is_preprint":false},{"pmid":"30627224","id":"PMC_30627224","title":"SP110 Polymorphisms Are Genetic Markers for Vulnerability to Latent and Active Tuberculosis Infection in Taiwan.","date":"2018","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/30627224","citation_count":23,"is_preprint":false},{"pmid":"22691368","id":"PMC_22691368","title":"SP110 gene polymorphisms and tuberculosis susceptibility: a systematic review and meta-analysis based on 10 624 subjects.","date":"2012","source":"Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/22691368","citation_count":21,"is_preprint":false},{"pmid":"21397050","id":"PMC_21397050","title":"Association of SP110 gene polymorphisms with susceptibility to tuberculosis in a Chinese population.","date":"2011","source":"Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/21397050","citation_count":21,"is_preprint":false},{"pmid":"22982295","id":"PMC_22982295","title":"Hepatic veno-occlusive disease with immunodeficiency (VODI): first reported case in the U.S. and identification of a unique mutation in Sp110.","date":"2012","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/22982295","citation_count":21,"is_preprint":false},{"pmid":"21536091","id":"PMC_21536091","title":"Genetic association study suggests a role for SP110 variants in lymph node tuberculosis but not pulmonary tuberculosis in north Indians.","date":"2011","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21536091","citation_count":15,"is_preprint":false},{"pmid":"22522001","id":"PMC_22522001","title":"Polymorphisms in SP110 are not associated with pulmonary tuberculosis in Indonesians.","date":"2012","source":"Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/22522001","citation_count":14,"is_preprint":false},{"pmid":"27873510","id":"PMC_27873510","title":"Certain Polymorphisms in SP110 Gene Confer Susceptibility to Tuberculosis: A Comprehensive Review and Updated Meta-Analysis.","date":"2017","source":"Yonsei medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/27873510","citation_count":13,"is_preprint":false},{"pmid":"29642903","id":"PMC_29642903","title":"Functional domains of SP110 that modulate its transcriptional regulatory function and cellular translocation.","date":"2018","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/29642903","citation_count":12,"is_preprint":false},{"pmid":"29430075","id":"PMC_29430075","title":"Polymorphisms in the SP110 and TNF-α Gene and Susceptibility to Pulmonary and Spinal Tuberculosis among Southern Chinese Population.","date":"2017","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/29430075","citation_count":12,"is_preprint":false},{"pmid":"28969051","id":"PMC_28969051","title":"Sp110 enhances macrophage resistance to Mycobacterium tuberculosis via inducing endoplasmic reticulum stress and inhibiting anti-apoptotic factors.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28969051","citation_count":11,"is_preprint":false},{"pmid":"25612917","id":"PMC_25612917","title":"The effects of SP110's associated genes on fresh cavitary pulmonary tuberculosis in Han Chinese population.","date":"2015","source":"Clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25612917","citation_count":11,"is_preprint":false},{"pmid":"17883869","id":"PMC_17883869","title":"Sp110 transcription is induced and required by Anaplasma phagocytophilum for infection of human promyelocytic cells.","date":"2007","source":"BMC infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/17883869","citation_count":9,"is_preprint":false},{"pmid":"28825155","id":"PMC_28825155","title":"Detection of Sp110 by Flow Cytometry and Application to Screening Patients for Veno-occlusive Disease with Immunodeficiency.","date":"2017","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28825155","citation_count":8,"is_preprint":false},{"pmid":"23448538","id":"PMC_23448538","title":"The role of hematopoietic stem cell transplantation in SP110 associated veno-occlusive disease with immunodeficiency syndrome.","date":"2013","source":"Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23448538","citation_count":8,"is_preprint":false},{"pmid":"17510920","id":"PMC_17510920","title":"The first prenatal diagnosis for veno-occlusive disease and immunodeficiency syndrome, an autosomal recessive condition associated with mutations in SP110.","date":"2007","source":"Prenatal diagnosis","url":"https://pubmed.ncbi.nlm.nih.gov/17510920","citation_count":8,"is_preprint":false},{"pmid":"32642571","id":"PMC_32642571","title":"Correlations between single nucleotide polymorphisms in bovine CD209, SLC11A1, SP110 and TLR2 genes and estimated breeding values for several traits in Spanish Holstein cattle.","date":"2020","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/32642571","citation_count":7,"is_preprint":false},{"pmid":"21033425","id":"PMC_21033425","title":"[Study on relation between Sp110 gene polymorphism and tuberculosis genetic susceptibility of Chongqing Han People].","date":"2010","source":"Wei sheng yan jiu = Journal of hygiene research","url":"https://pubmed.ncbi.nlm.nih.gov/21033425","citation_count":7,"is_preprint":false},{"pmid":"27623071","id":"PMC_27623071","title":"SP110 and PMP22 polymorphisms are associated with tuberculosis risk in a Chinese-Tibetan population.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27623071","citation_count":6,"is_preprint":false},{"pmid":"39162523","id":"PMC_39162523","title":"Transcriptional regulators SP110 and SP140 modulate inflammatory response genes in Mycobacterium tuberculosis-infected human macrophages.","date":"2024","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/39162523","citation_count":5,"is_preprint":false},{"pmid":"38938101","id":"PMC_38938101","title":"UBR7 E3 Ligase Suppresses Interferon-β Mediated Immune Signaling by Targeting Sp110 in Hepatitis B Virus-Induced Hepatocellular Carcinoma.","date":"2024","source":"ACS infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/38938101","citation_count":4,"is_preprint":false},{"pmid":"36249417","id":"PMC_36249417","title":"Polymorphisms in the ASAP1 and SP110 Genes and Its Association with the Susceptibility to Pulmonary Tuberculosis in a Mongolian Population.","date":"2022","source":"Journal of immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/36249417","citation_count":3,"is_preprint":false},{"pmid":"27865405","id":"PMC_27865405","title":"Identification of SP110 in horse (Equus caballus): Isolation of novel splice variants and evidence of activation effects on macrophages.","date":"2016","source":"Tuberculosis (Edinburgh, Scotland)","url":"https://pubmed.ncbi.nlm.nih.gov/27865405","citation_count":3,"is_preprint":false},{"pmid":"35308005","id":"PMC_35308005","title":"HSP60, SP110 and TNF-α expression in Chlamydia pneumoniae-positive versus Chlamydia pneumoniae-negative atherosclerotic plaques.","date":"2021","source":"Polish journal of pathology : official journal of the Polish Society of Pathologists","url":"https://pubmed.ncbi.nlm.nih.gov/35308005","citation_count":2,"is_preprint":false},{"pmid":"41826696","id":"PMC_41826696","title":"An SP110-SP100 axis is a critical regulator of promyelocytic leukaemia body dynamics and mitotic fidelity.","date":"2026","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/41826696","citation_count":1,"is_preprint":false},{"pmid":"38951481","id":"PMC_38951481","title":"SP110 Could be Used as a Potential Predictive and Therapeutic Biomarker for Oral Cancer.","date":"2024","source":"Molecular biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/38951481","citation_count":1,"is_preprint":false},{"pmid":"26995495","id":"PMC_26995495","title":"Molecular characterization of Sp110 gene in pigs.","date":"2016","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/26995495","citation_count":1,"is_preprint":false},{"pmid":"32395362","id":"PMC_32395362","title":"Unique Mutation in SP110 Resulting in Hepatic Veno-Occlusive Disease with Immunodeficiency.","date":"2020","source":"Case reports in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/32395362","citation_count":1,"is_preprint":false},{"pmid":"41382217","id":"PMC_41382217","title":"Species-specific alternative splicing of SP110 drives tuberculosis susceptibility in cattle.","date":"2025","source":"Veterinary research","url":"https://pubmed.ncbi.nlm.nih.gov/41382217","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.19.677270","title":"The C3HeB/FeJ Kramnik mouse as a model to investigate the efficacy of therapeutic tuberculosis interventions","date":"2025-09-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.19.677270","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23508,"output_tokens":4020,"usd":0.065412,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11932,"output_tokens":4476,"usd":0.08578,"stage2_stop_reason":"end_turn"},"total_usd":0.151192,"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\": 2000,\n      \"finding\": \"SP110 localizes to PML-Sp100 nuclear bodies in ATRA-treated NB4 cells, and an SP110 DNA-binding domain fusion protein activates transcription of a reporter gene in transfected mammalian cells. SP110 also markedly increases ATRA-mediated expression of a reporter gene containing a retinoic acid response element, indicating SP110 functions as a nuclear hormone receptor transcriptional coactivator.\",\n      \"method\": \"Immunofluorescence localization, transfection-based luciferase/reporter assay, ATRA treatment of NB4 cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunofluorescence tied to functional consequence, reporter assay in mammalian cells; single lab with two orthogonal methods\",\n      \"pmids\": [\"10913195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Loss-of-function mutations in SP110 (truncating and other mutations) cause veno-occlusive disease with immunodeficiency (VODI), characterized by severe hypogammaglobulinemia, combined T and B cell immunodeficiency, absent germinal centers, absent plasma cells, and hepatic veno-occlusive disease, establishing SP110 as required for normal immune development.\",\n      \"method\": \"Human genetics/Sanger sequencing of SP110 in VODI patients; clinical and immunological phenotyping\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple independent truncating mutations in SP110 segregating with disease phenotype, replicated in multiple families; human genetics with clear molecular and cellular phenotype\",\n      \"pmids\": [\"16648851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SP110 deficiency in human B cells compromises their ability to respond to T cell-dependent stimuli (CD40L, IL-21) and differentiate into immunoglobulin-secreting plasma cells in vitro, as demonstrated using cells from VODI patients with SP110 mutations. Analysis of 4 new alleles confirmed VODI is caused by reduced functional SP110 protein levels. Mutant SP110 proteins are subject to enhanced proteasomal degradation.\",\n      \"method\": \"Immunofluorescence of transfected mutant proteins in HEp-2 cells; flow cytometry B-cell phenotyping; B-cell stimulation assays; gene expression arrays\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (protein localization, B-cell functional assay, gene expression profiling) in a single rigorous study; confirmed reduced SP110 protein as the mechanistic basis\",\n      \"pmids\": [\"22621957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SP110 is SUMO1-modified and resides in PML nuclear bodies in a SUMOylated state. During HBV infection, HBx protein interacts with SP110 and drives deSUMOylation-dependent release of SP110 from PML-NBs. SP110 knockdown reduces viral DNA load by activating the type I interferon response pathway. SP110 regulates HBx direct target genes, and the SP110-HBx interaction is required for HBx recruitment to the promoters of co-regulated genes, where HBx modulates recruitment of p300/HDAC1 to alter host gene expression in favor of viral persistence.\",\n      \"method\": \"Co-immunoprecipitation (SP110-HBx interaction), immunofluorescence (SP110 localization), SUMO1 modification assay, SP110 knockdown with viral load quantification, ChIP (HBx and p300/HDAC1 promoter recruitment)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP for HBx interaction, direct localization with functional consequence (SUMO-dependent PML-NB exit), ChIP for promoter recruitment, KD with defined phenotype; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29046350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SP110 interacts with HSP5 (Hspa5/BiP) to activate endoplasmic reticulum (ER) stress-induced apoptosis in mouse macrophages, which is essential for Sp110-enhanced resistance to M. tuberculosis. SP110 also interacts with RNA-binding protein Ncl (nucleolin) and promotes its degradation, thereby downregulating Bcl2 (normally stabilized by Ncl). Additionally, SP110 promotes degradation of ribosomal protein Rps3a, upregulating pro-apoptotic PARP activity. Inhibition of the ER stress pathway abolished SP110-enhanced macrophage apoptosis and increased intracellular Mtb survival.\",\n      \"method\": \"Proteomics/MS (253 interacting proteins identified), Co-immunoprecipitation, ER stress pathway inhibition, macrophage overexpression, Mtb survival assay, transgenic cattle macrophages\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based interactome with functional follow-up (ER stress inhibition, KO/overexpression phenotype); single lab with multiple methods but functional mechanism validated in transgenic cattle macrophages\",\n      \"pmids\": [\"28969051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The N-terminal fragment (amino acids 1–276) of SP110 interacts with p50 (an NF-κB subunit) in the cytoplasm, and this interaction is required for downregulation of p50-driven TNF-α promoter activity. Different SP110 isoforms have distinct effects on NF-κB-mediated transcription. The middle region of SP110 contains a nucleolar localization signal (NoLS) with monopartite and bipartite NLS elements that directs SP110 to the nucleolus under certain conditions, whereas the middle and C-terminal regions also govern localization to other cellular compartments.\",\n      \"method\": \"Luciferase reporter assay (deletion mutants), co-immunoprecipitation, confocal microscopy (GFP-tagged SP110 mutants), Western blotting\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deletion mutagenesis combined with reporter assay and Co-IP identifies functional domains; confocal microscopy for localization; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29642903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBR7 E3 ubiquitin ligase ubiquitinates SP110 at critical residues within its SAND domain. This ubiquitination of SP110 downregulates genes in the type I interferon response pathway. Wild-type but not ubiquitination-defective mutant SP110 is recruited to type I interferon response pathway gene promoters. Silencing UBR7 induces IRF7 phosphorylation and augments IFN-β and downstream ISGs, confirming that UBR7-mediated SP110 ubiquitination suppresses IFN-β immune signaling during HBV infection.\",\n      \"method\": \"In vitro ubiquitination assay, RNA-seq (UBR7/SP110 knockdown), Co-IP (UBR7-SP110 interaction), site-directed mutagenesis (ubiquitination-defective SP110), ChIP (SP110 promoter recruitment), scRNA-seq patient data analysis\",\n      \"journal\": \"ACS infectious diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro ubiquitination assay with mutagenesis of SAND domain residues, ChIP for promoter recruitment of wild-type vs mutant SP110, KD phenotype with multiple orthogonal methods; single lab\",\n      \"pmids\": [\"38938101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In M. tuberculosis-infected THP-1 macrophages, depletion of SP110 (and/or SP140) impairs induction of inflammatory response genes including type I IFN response genes, while genes related to phosphorylation are upregulated upon SP110/SP140 knockdown. This establishes human SP110 as a positive transcriptional regulator of inflammatory/IFN response genes during Mtb infection.\",\n      \"method\": \"Genome-wide transcriptional profiling, RT-qPCR, ELISA, siRNA knockdown of SP110 and/or SP140 in THP-1 macrophages infected with M. tuberculosis\",\n      \"journal\": \"Microbiology spectrum\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide transcriptomics plus orthogonal RT-qPCR and ELISA validation; single lab but multiple methods\",\n      \"pmids\": [\"39162523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SP110 regulates transcription of macrophage genes involved in immune responses, apoptosis, defense, and inflammatory responses upon Mtb infection. SP110 upregulates the pro-apoptotic factor Bmf by inhibiting miR-125a, and forced Bmf expression induces macrophage apoptosis, placing SP110 upstream of a miRNA-Bmf-apoptosis axis.\",\n      \"method\": \"Integrated transcriptome analysis, miRNA expression profiling, Bmf overexpression/knockdown, apoptosis assay in RAW264.7 macrophages\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptome plus mechanistic follow-up (miR-125a inhibition, Bmf forced expression with apoptosis readout); single lab with two orthogonal approaches\",\n      \"pmids\": [\"26912204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SP110 is a potent inhibitor of type I interferon-driven cell death that counteracts a toxic activity of SP100. Loss of SP110 leads to mitotic retention of SP100 and PML nuclear bodies, which associate with segregating chromosomes, causing micronucleus formation, DNA damage, and genotoxic cell death. Cryo-EM and AlphaFold modelling combined with cellular biochemistry demonstrate that SP110 dissolves toxic SP100 oligomers via direct interactions between their CARD (caspase activation and recruitment) domains, establishing a structural mechanism for PML body disassembly during mitosis.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 genetic screen (triphosphorylated RNA stimulation), cryo-electron microscopy, AlphaFold structural modelling, cellular biochemistry (Co-IP, domain mapping), live-cell imaging (mitotic SP100/PML retention), micronucleus assay, DNA damage assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus AlphaFold plus cellular biochemistry plus genetic screen with defined cell death phenotype; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"41826696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SP110 expression is induced by Anaplasma phagocytophilum infection of human HL-60 promyelocytic cells, and siRNA-mediated knockdown of SP110 reduces A. phagocytophilum infection and multiplication, demonstrating that SP110 is required for this intracellular pathogen to establish infection.\",\n      \"method\": \"Real-time RT-PCR, RNA interference (siRNA knockdown), quantitative PCR of bacterial load\",\n      \"journal\": \"BMC infectious diseases\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (RNAi + qPCR); no mechanistic pathway placement beyond requirement for infection\",\n      \"pmids\": [\"17883869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Transgenic cattle with SP110 knocked into their genome via TALE nickase-mediated homologous recombination control growth and multiplication of Mycobacterium bovis, shift cell death from necrosis to apoptosis upon infection, and resist low-dose M. bovis transmission in vivo, demonstrating that SP110 expression promotes the apoptotic pathway and confers tuberculosis resistance at the organismal level.\",\n      \"method\": \"TALEN-mediated genome knockin (homologous recombination), in vitro and in vivo M. bovis challenge, apoptosis/necrosis pathway analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined genetic knockin with in vivo challenge and mechanistic pathway determination (apoptosis vs necrosis); single study with multiple readouts\",\n      \"pmids\": [\"25733846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Species-specific alternative splicing of the bovine SP110 gene produces a truncated bSP110c variant that lacks the SAND domain required for anti-tuberculosis function. This truncated isoform predominates in dairy cattle due to a ruminant-specific absence of a pre-SAND exon, which promotes bSP110c splicing. Substituting the pre-SAND region with human or equine sequences suppresses bSP110c and increases bSP110a/b expression, while bSP110c shows significantly reduced resistance to M. bovis compared to bSP110a and bSP110b.\",\n      \"method\": \"RT-PCR splice variant characterization, minigene splicing assay, M. bovis infection assay comparing isoforms, domain deletion analysis (SAND domain), sequence substitution experiments\",\n      \"journal\": \"Veterinary research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional comparison of splice variants in infection assay plus mechanistic minigene splicing experiments; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41382217\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SP110 is an interferon-inducible, leukocyte-enriched nuclear body protein that resides in PML-SP100 nuclear bodies in a SUMO1-modified state, functions as a transcriptional coactivator/regulator (including of NF-κB and type I IFN response genes) through its N-terminal domain interaction with p50 and its SAND domain, dissolves toxic SP100 oligomers via CARD-domain interactions to enable PML body disassembly during mitosis, promotes macrophage apoptosis over necrosis upon mycobacterial infection via ER stress (Hspa5 interaction), Bcl2 suppression (Ncl degradation), and PARP activation, and is subject to ubiquitination by UBR7 (at SAND domain residues) and to HBx-driven deSUMOylation that releases it from PML bodies to modulate host gene expression during HBV infection; loss-of-function mutations cause VODI primary immunodeficiency with impaired B-cell differentiation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SP110 is an interferon-inducible nuclear body protein that acts as a transcriptional regulator within the PML-SP100 nuclear body system and as a key controller of innate immune and cell death programs during intracellular infection [#0, #9]. It localizes to PML-SP100 nuclear bodies and functions as a transcriptional coactivator, including of retinoic-acid-responsive promoters via its DNA-binding domain [#0], and modulates NF-\\u03baB output through an N-terminal (aa 1\\u2013276) interaction with the p50 subunit that downregulates p50-driven TNF-\\u03b1 promoter activity, with distinct isoforms exerting distinct effects [#5]. SP110 governs PML body dynamics by dissolving toxic SP100 oligomers through direct CARD-CARD domain interactions, enabling PML body disassembly during mitosis; loss of SP110 causes mitotic retention of SP100/PML on segregating chromosomes, micronucleus formation, DNA damage, and type I interferon-driven genotoxic cell death [#9]. During mycobacterial infection SP110 reprograms macrophage death from necrosis toward apoptosis through ER stress activation via Hspa5/BiP, Bcl2 suppression through nucleolin degradation, PARP activation via Rps3a degradation, and a miR-125a\\u2013Bmf pro-apoptotic axis, and this activity confers tuberculosis resistance at the organismal level [#4, #8, #11]. As a positive transcriptional regulator of inflammatory and type I IFN response genes, SP110 is recruited to IFN-pathway promoters, an activity opposed by UBR7-mediated ubiquitination at SAND-domain residues and exploited during HBV infection, where HBx drives deSUMOylation-dependent release of SP110 from PML bodies to remodel host gene expression [#3, #6, #7]. Loss-of-function mutations that reduce functional SP110 protein cause veno-occlusive disease with immunodeficiency (VODI), with impaired B-cell differentiation into immunoglobulin-secreting plasma cells [#1, #2].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established SP110 as a PML-SP100 nuclear body resident with intrinsic transcriptional coactivator activity, framing it as a regulator of gene expression rather than a passive structural protein.\",\n      \"evidence\": \"Immunofluorescence localization in ATRA-treated NB4 cells plus reporter assays in transfected mammalian cells\",\n      \"pmids\": [\"10913195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct endogenous target genes not identified\", \"Mechanism of coactivation at native promoters undefined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the physiological requirement for SP110 by linking loss-of-function mutations to VODI, demonstrating SP110 is essential for normal immune development.\",\n      \"evidence\": \"Sanger sequencing of SP110 in VODI families with clinical and immunological phenotyping\",\n      \"pmids\": [\"16648851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular pathway connecting SP110 loss to B-cell failure unresolved\", \"Cause of hepatic veno-occlusive disease not mechanistically explained\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed SP110 is induced by and required for an intracellular bacterial infection, implicating it in host-pathogen interactions.\",\n      \"evidence\": \"RT-PCR and siRNA knockdown with bacterial load quantification in HL-60 cells infected with Anaplasma phagocytophilum\",\n      \"pmids\": [\"17883869\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single method (RNAi + qPCR) without mechanistic pathway placement\", \"No identification of how SP110 supports infection\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved the molecular basis of VODI as reduced functional SP110 protein and connected it to a defect in T-dependent B-cell differentiation into plasma cells.\",\n      \"evidence\": \"Mutant protein expression in HEp-2 cells, flow cytometry, B-cell stimulation assays, and gene expression arrays from VODI patients\",\n      \"pmids\": [\"22621957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific transcriptional targets driving plasma cell differentiation not defined\", \"Link between enhanced proteasomal degradation and B-cell phenotype not directly demonstrated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated at the organismal level that SP110 shifts infected-cell death from necrosis to apoptosis and confers tuberculosis resistance.\",\n      \"evidence\": \"TALEN-mediated SP110 knockin transgenic cattle with in vitro/in vivo M. bovis challenge and apoptosis/necrosis analysis\",\n      \"pmids\": [\"25733846\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular effectors of the apoptotic shift not identified in this study\", \"Generalizability beyond bovine system not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed SP110 upstream of a defined pro-apoptotic axis, showing it induces Bmf by inhibiting miR-125a to drive macrophage apoptosis during Mtb infection.\",\n      \"evidence\": \"Integrated transcriptome and miRNA profiling with Bmf manipulation and apoptosis assays in RAW264.7 macrophages\",\n      \"pmids\": [\"26912204\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of SP110 to relevant promoters not shown\", \"How SP110 represses miR-125a undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified the biochemical mechanisms by which SP110 enforces apoptosis over necrosis: ER stress via Hspa5, Bcl2 suppression through nucleolin degradation, and PARP activation via Rps3a degradation.\",\n      \"evidence\": \"MS interactome (253 proteins), Co-IP, ER stress inhibition, and Mtb survival assays in macrophages including transgenic cattle cells\",\n      \"pmids\": [\"28969051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SP110 promotes target degradation not defined\", \"Direct vs indirect nature of some interactions from large MS set uncertain\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed SUMO-dependent control of SP110 PML-body residence and its exploitation by HBV, where HBx interaction releases SP110 to remodel host transcription and aid viral persistence.\",\n      \"evidence\": \"Reciprocal Co-IP, SUMO1 modification assay, knockdown with viral load, and ChIP for HBx and p300/HDAC1 promoter recruitment\",\n      \"pmids\": [\"29046350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO ligase/protease controlling SP110 modification not identified\", \"Full set of co-regulated host genes incompletely mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped functional domains of SP110, defining an N-terminal p50-interacting region that suppresses NF-\\u03baB target activity and a middle-region NoLS controlling subcellular distribution.\",\n      \"evidence\": \"Deletion-mutant luciferase reporters, Co-IP, and confocal microscopy of GFP-tagged SP110 variants\",\n      \"pmids\": [\"29642903\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological conditions triggering nucleolar localization unclear\", \"Isoform-specific transcriptional effects not linked to defined target genes\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established SP110 as a positive transcriptional regulator of inflammatory and type I IFN response genes in human macrophages during Mtb infection.\",\n      \"evidence\": \"Genome-wide transcriptomics with RT-qPCR and ELISA validation following SP110/SP140 siRNA knockdown in THP-1 macrophages\",\n      \"pmids\": [\"39162523\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect promoter targets not distinguished from SP140 contribution\", \"Mechanism of transcriptional activation not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a post-translational brake on SP110 transcriptional activity: UBR7 ubiquitinates SAND-domain residues to block SP110 recruitment to type I IFN gene promoters and suppress IFN-\\u03b2 signaling.\",\n      \"evidence\": \"In vitro ubiquitination assay with SAND-residue mutagenesis, Co-IP, RNA-seq, and ChIP of wild-type vs ubiquitination-defective SP110\",\n      \"pmids\": [\"38938101\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conditions regulating UBR7-SP110 ubiquitination not defined\", \"Structural impact of SAND ubiquitination on chromatin recruitment unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided a structural mechanism for SP110 in PML body biology, showing it dissolves toxic SP100 CARD oligomers to enable mitotic PML body disassembly and prevent genotoxic IFN-driven cell death.\",\n      \"evidence\": \"Genome-wide CRISPR screen, cryo-EM, AlphaFold modelling, domain-mapping biochemistry, live-cell imaging, and micronucleus/DNA-damage assays\",\n      \"pmids\": [\"41826696\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CARD-CARD dissolution is regulated through the cell cycle not detailed\", \"Connection to SP110's transcriptional roles not integrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed isoform identity dictates SP110 anti-tuberculosis function, with a SAND-lacking bovine splice variant losing activity due to a ruminant-specific exon arrangement.\",\n      \"evidence\": \"RT-PCR splice variant characterization, minigene splicing assays, M. bovis infection comparison of isoforms, and sequence substitution experiments\",\n      \"pmids\": [\"41382217\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relevance to human SP110 isoform regulation not established\", \"Molecular role of the SAND domain in anti-Mtb activity not directly demonstrated here\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SP110's transcriptional coactivator activity, PML-body structural role, and pro-apoptotic infection responses are mechanistically unified, and what governs the SUMO/ubiquitin switching of its localization and activity, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model linking nuclear body disassembly to transcriptional output\", \"Upstream signals controlling SP110 SUMOylation/ubiquitination undefined\", \"Direct genome-wide SP110 binding map absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 7, 6]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 8, 9, 11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"complexes\": [\"PML-SP100 nuclear body\"],\n    \"partners\": [\"SP100\", \"HBx\", \"NFKB1\", \"HSPA5\", \"NCL\", \"UBR7\", \"SP140\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}