Affinage

SPIC

Transcription factor Spi-C · UniProt Q8N5J4

Length
248 aa
Mass
29.2 kDa
Annotated
2026-04-28
41 papers in source corpus 18 papers cited in narrative 18 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SPIC is an ETS-family transcription factor that orchestrates iron homeostasis, myeloid cell fate, and B-cell developmental checkpoints through context-dependent transcriptional activation and repression. In monocytes and macrophages, heme-driven proteasomal degradation of the repressor BACH1 derepresses SPIC expression, which is essential for differentiation of red pulp macrophages and bone marrow macrophages that recycle iron from senescent erythrocytes via ferroportin; TLR/NF-κB signaling further induces SPIC to suppress pro-inflammatory cytokines, while IFN-γ/STAT1 antagonizes this pathway (PMID:19037245, PMID:24630724, PMID:32610126). In pre-B cells, RAG-induced DNA double-strand breaks activate a SPIC/BCLAF1 complex that displaces PU.1 genome-wide, represses Nfkb1, Rag1, and Igκ transcription, and enforces the large-to-small pre-B cell transition, while in mature B cells SPIC opposes Spi-B to regulate plasma cell differentiation and cooperates with STAT6 to stimulate IgE germline transcription (PMID:31644907, PMID:37195219, PMID:25769919, PMID:16647686). SPIC also functions in embryonic stem cells, where it stabilizes NANOG binding at enhancers controlling one-carbon metabolism genes and modulates histone methylation through SAM-to-SAH flux (PMID:37595034).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1999 High

    Identification of SPIC as a new ETS-family member established that the PU.1/Spi-B subfamily contained a third factor with similar DNA-binding specificity but potentially distinct functions.

    Evidence Yeast one-hybrid screen, EMSA, methylation interference, and reporter assay in HeLa cells

    PMID:10187812

    Open questions at the time
    • No in vivo function determined
    • Expression pattern across tissues not fully characterized
    • Endogenous target genes unknown
  2. 2003 High

    Mapping of an N-terminal acidic transactivation domain and demonstration that SPIC cannot form ternary complexes with PIP on the Igλ enhancer distinguished SPIC mechanistically from PU.1.

    Evidence Deletion/point mutagenesis of transactivation domain with reporter assays and gel shift ternary complex assay

    PMID:12749910

    Open questions at the time
    • Whether SPIC uses alternative co-activators not tested
    • Structural basis for inability to recruit PIP unknown
  3. 2006 Medium

    Discovery that SPIC physically interacts with STAT6 and synergistically activates IgE germline transcription revealed a first functional partnership linking SPIC to humoral immune regulation.

    Evidence Yeast two-hybrid, co-immunoprecipitation in COS7, reporter assay for Iε promoter

    PMID:16647686

    Open questions at the time
    • Interaction not confirmed in primary B cells
    • Whether SPIC-STAT6 interaction occurs on endogenous chromatin not tested
  4. 2008 High

    Genetic knockout demonstrated that SPIC is uniquely required for red pulp macrophage development and iron recycling, establishing its non-redundant role relative to PU.1 and Spi-B, while transgenic overexpression in B cells revealed dose-dependent repression of BCR signaling components.

    Evidence Spic−/− mice with retroviral rescue, phagocytosis and iron staining assays; Eμ-Spi-C transgenic mice with flow cytometry and proliferation assays

    PMID:18792411 PMID:19037245

    Open questions at the time
    • Transcriptional targets in RPM not mapped genome-wide
    • Whether B-cell repression is direct or indirect at individual loci unclear
  5. 2014 High

    Identification of the heme–BACH1–SPIC axis resolved how environmental iron sensing is transduced into a transcriptional program: heme triggers proteasomal BACH1 degradation via cysteine-proline motifs, derepressing Spic to drive RPM and bone marrow macrophage differentiation.

    Evidence Spic−/− and hemolysis mouse models, BACH1 CP-motif mutant constructs, proteasome inhibitor experiments

    PMID:24630724

    Open questions at the time
    • Whether additional repressors besides BACH1 regulate Spic in non-macrophage lineages not addressed
    • Direct BACH1 binding to Spic locus not demonstrated by ChIP
  6. 2015 Medium

    Genetic epistasis between Spic and Spib showed that SPIC opposes Spi-B by repressing Nfkb1 transcription, establishing a balancing mechanism within the subfamily that tunes B-cell output.

    Evidence Spib−/−Spic+/− mice, reporter assay, gene expression analysis

    PMID:25769919

    Open questions at the time
    • Whether SPIC directly binds the Nfkb1 promoter in primary B cells not shown by ChIP
    • Downstream NF-κB targets affected not mapped
  7. 2019 High

    Genome-wide ChIP-seq revealed that RAG-induced DNA breaks trigger a SPIC/BCLAF1 complex that displaces PU.1 from regulatory elements, represses SYK, and enforces the pre-B cell transition, connecting DNA damage signaling to lineage progression.

    Evidence ChIP-seq, co-immunoprecipitation, gene expression in pre-B cells with RAG-induced DSBs

    PMID:31644907

    Open questions at the time
    • How DNA break signals induce SPIC protein or complex assembly not fully elucidated
    • Structural basis of SPIC-BCLAF1 interaction unknown
  8. 2019 Medium

    TLR signaling was shown to couple erythrophagocytosis-derived heme with SPIC induction in splenic macrophages, which then drives Gdf15 and Bmp4 expression to initiate stress erythropoiesis, extending SPIC's role beyond iron recycling to erythroid regeneration.

    Evidence Mouse sterile inflammation model, erythrophagocytosis assay, gene expression

    PMID:31506384

    Open questions at the time
    • Whether SPIC directly binds Gdf15/Bmp4 regulatory regions not established
    • Relevance to human stress erythropoiesis not tested
  9. 2020 Medium

    Multiple studies established SPIC as an NF-κB-induced anti-inflammatory effector in macrophages that promotes ferroportin expression and iron efflux while being antagonized by IFN-γ/STAT1, and as a regulator of osteoclast differentiation and plasma cell fate.

    Evidence Genetic mouse models with NF-κB/STAT1 pathway manipulation; RANKL-stimulated BMMs with kinase inhibitors and localization assays; Spib−/−Spic+/− mice with ChIP-seq for Bach2

    PMID:32341419 PMID:32457757 PMID:32610126

    Open questions at the time
    • Direct SPIC binding at ferroportin locus not mapped
    • Osteoclast findings from single lab without in vivo bone phenotype
    • SPIC nuclear translocation mechanism in osteoclasts not fully defined
  10. 2022 Medium

    Promoter dissection revealed that NF-κB binding is required for Spic promoter activity and that Bach2 represses Spic through an upstream regulatory region in B cells, while external B-cell activating signals downregulate Spic partly through actin-dependent mechanisms.

    Evidence Promoter deletion/mutation reporter assay, RT-qPCR, cytochalasin treatment

    PMID:38285436

    Open questions at the time
    • Actin-dependent repression mechanism molecularly undefined
    • Whether Bach2 directly binds the identified upstream element not confirmed by ChIP
  11. 2023 Medium

    Three studies expanded SPIC's functional scope: it represses Igκ rearrangement by directly opposing PU.1 at Rag1 and Igκ loci in pre-B cells; it stabilizes NANOG on enhancers of one-carbon metabolism genes in ESCs to control histone methylation; and its zebrafish ortholog drives metaphocyte generation for barrier immunity.

    Evidence ChIP plus inducible expression in pre-B cells and Spic−/− mice; ChIP, metabolomics, and histone modification in ESCs; zebrafish spic knockout with lineage tracing

    PMID:37148242 PMID:37195219 PMID:37595034

    Open questions at the time
    • ESC function awaits confirmation in mammalian embryonic development in vivo
    • Whether metaphocyte specification by Spic is conserved in mammals unknown
    • SPIC occupancy at Rag1 in primary small pre-B cells not validated genome-wide
  12. 2026 Medium

    Demonstration that m6A methylation by ZC3H13 destabilizes Spic mRNA revealed a post-transcriptional layer of SPIC regulation, with SPIC protein levels controlling NF-κB-dependent inflammatory responses in macrophages.

    Evidence siRNA knockdown/co-silencing of Zc3h13 and Spic in macrophages, m6A and mRNA stability assays, in vivo LPS model

    PMID:41847860

    Open questions at the time
    • Specific m6A sites on Spic mRNA not mapped
    • Whether other m6A readers/erasers participate not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of SPIC's context-dependent switching between transcriptional activation and repression, how DNA damage signals post-translationally activate SPIC in pre-B cells, and whether SPIC's role in ESC chromatin and zebrafish metaphocytes reflects conserved mammalian developmental functions.
  • No crystal or cryo-EM structure available
  • Post-translational modifications controlling SPIC activity largely uncharacterized
  • No genome-wide target comparison across cell types (macrophage vs. B cell vs. ESC)

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 6
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-1266738 Developmental Biology 5 R-HSA-168256 Immune System 5 R-HSA-382551 Transport of small molecules 3
Partners
BACH1BACH2BCLAF1NANOGSPI1SPIBSTAT6
Complex memberships
SPIC-BCLAF1 complex

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Spi-C is a novel ETS transcription factor most closely related to PU.1 and Spi-B within the DNA-binding ETS domain, isolated by yeast one-hybrid screening. It binds DNA similarly to PU.1 (assessed by methylation interference, band-shift, and site selection analysis) and activates transcription of a kappaY element reporter gene upon co-transfection of HeLa cells. Yeast one-hybrid screen, methylation interference, EMSA (band-shift), site selection analysis, reporter gene co-transfection The Journal of biological chemistry High 10187812
2003 SPI-C contains an acidic transactivation domain located at the N-terminus; mutation of four aspartic acid residues to alanines reduces transactivation activity to that of the DNA-binding domain alone. Unlike PU.1, SPI-C cannot form a ternary complex with the co-activator PIP on the Ig lambda light chain enhancer element. Deletion and point mutation analysis of transactivation domain, reporter assays, gel shift/ternary complex assay Molecular immunology High 12749910
2006 SPI-C physically interacts with the C-terminus of STAT6, confirmed by yeast two-hybrid and co-immunoprecipitation in transfected COS7 cells. This interaction is functional: SPI-C and STAT6 synergistically stimulate IL-4-induced Iε (IgE germline) transcription only when both proteins are DNA-bound. Yeast two-hybrid, co-immunoprecipitation, reporter gene assay Biochemical and biophysical research communications Medium 16647686
2008 Spi-C selectively controls the development of red pulp macrophages (RPM) in a cell-autonomous manner. Spic−/− mice lack RPM but have normal monocytes and other tissue macrophages; retroviral Spi-C expression in bone marrow cells corrects this defect. Loss of RPM results in failure to phagocytose senescent red blood cells and iron overload localized to splenic red pulp. Knockout mouse model (Spic−/−), retroviral complementation in bone marrow, flow cytometry, phagocytosis assay, iron staining Nature High 19037245
2008 Transgenic overexpression of Spi-C in B cells impairs B-cell development and function by downregulating several BCR signaling mediators (including SYK and BLNK) and upregulating an inhibitor of BCR signaling, resulting in poor proliferative responses to anti-IgM or anti-CD40. B-cell-specific transgenic mouse (Eμ-Spi-C), flow cytometry, real-time RT-PCR, in vitro proliferation assay European journal of immunology Medium 18792411
2010 Spi-C, together with PU.1 and Spi-B, directly activates transcription of the Fcer2a gene (encoding CD23) to promote follicular B cell differentiation. Eμ-Spi-C transgene expression partially rescues CD23+ follicular B cell frequencies in Sfpi1+/−Spib−/− mice. Transgenic rescue experiment, in vitro reporter assay, chromatin immunoprecipitation (ChIP), gene expression analysis Journal of immunology High 21057087
2014 Heme induces proteasome-dependent degradation of the transcriptional repressor BACH1, derepressing Spic expression in monocytes to drive their differentiation into iron-recycling red pulp macrophages and bone marrow macrophages. Cysteine-proline dipeptide motifs in BACH1 are required for heme-dependent degradation. Spic also governs development of F4/80+VCAM1+ bone marrow macrophages. Genetic mouse models (Spic−/−, hemolysis models), proteasome inhibitor experiments, BACH1 mutant constructs (CP motif mutations), flow cytometry, gene expression Cell High 24630724
2015 Spi-C functions as a negative regulator of B-cell development and function by repressing the Nfkb1 gene (encoding p50), opposing Spi-B which directly activates Nfkb1. Heterozygous loss of Spic in Spib−/− mice rescues B-cell frequencies, absolute numbers, and proliferative responses. Genetic epistasis (Spib−/−Spic+/− mice), reporter gene assay, gene expression analysis Journal of immunology Medium 25769919
2019 RAG-generated DNA double-strand breaks in pre-B cells activate a SPIC/BCLAF1 transcription factor complex that displaces PU.1 genome-wide, represses SYK tyrosine kinase expression, and enforces the large-to-small pre-B cell transition. SPIC recruits BCLAF1 to gene-regulatory elements controlling key B-cell developmental genes. ChIP-seq, co-immunoprecipitation, gene expression analysis, SPIC/BCLAF1 complex characterization in pre-B cells with RAG-induced DSBs Cell reports High 31644907
2019 TLR signaling induces stress erythropoiesis by promoting erythrophagocytosis in splenic macrophages, which enables heme-dependent SPI-C expression. Elevated SPI-C, coupled with TLR signaling, then drives expression of Gdf15 and Bmp4 to initiate expansion of stress erythroid progenitors in the spleen. Mouse model of sterile inflammation, TLR signaling studies, erythrophagocytosis assay, gene expression analysis, cytokine treatment of progenitors Science signaling Medium 31506384
2020 TLR signaling induces Spic expression in patrolling monocytes and tissue macrophages via an NF-κB-dependent mechanism. SPIC then downregulates pro-inflammatory cytokines and promotes iron efflux by regulating ferroportin expression. Interferon-gamma blocks Spic expression in a STAT1-dependent manner. Genetically engineered mouse models, primary macrophage cultures, NF-κB/STAT1 pathway inhibition, ferroportin expression assay Cell reports High 32610126
2020 RANKL stimulation induces nuclear translocation of Spi-C (from cytoplasm to nucleus) in bone marrow-derived monocytes/macrophages in a p38 MAPK- and PI3K-dependent manner. Spi-C positively regulates osteoclast differentiation by promoting expression of NFATc1, RANK, and TRAP, and regulates actin ring formation and bone resorption by controlling DC-STAMP and d2-ATPase expression. Spi-C knockdown and overexpression in BMMs, TRAP staining, actin ring assay, bone resorption assay, kinase inhibitor studies, immunofluorescence for localization Experimental & molecular medicine Medium 32341419
2020 Spi-B and Spi-C differentially regulate Bach2 expression; ChIP-seq and reporter gene analyses show opposing effects on Bach2 transcription, with Spi-B and Spi-C having different regulatory impacts on plasma cell differentiation. Heterozygosity for Spic in Spib−/− mice rescues IgG1 secondary antibody responses and restores plasma cell differentiation kinetics. Genetic epistasis (Spib−/−Spic+/− mice), ChIP-seq, reporter gene analysis, gene expression analysis Frontiers in immunology Medium 32457757
2022 The Spic promoter has unidirectional transcriptional activity reduced by mutation of an NF-κB binding site. In B cells, Spic expression is repressed by an upstream regulatory region interacting with heme-binding regulator Bach2. External signals (BAFF+IL-4+IL-5, anti-IgM, LPS) downregulate Spic, partly through actin cytoskeleton-dependent mechanisms. Promoter deletion/mutation analysis, reporter assay, RT-qPCR, cytochalasin treatment, regulatory element identification ImmunoHorizons Medium 38285436
2023 Spi-C negatively regulates Igκ rearrangement in small pre-B cells by repressing both Igκ transcription and Rag1 transcription, opposing PU.1 which activates both. ChIP analysis identified Spi-C and PU.1 binding sites in the Rag1 promoter region. Inducible expression system in pre-B cell line, Spic−/− mice, RT-qPCR, ChIP analysis Journal of immunology Medium 37195219
2023 SPIC binds to enhancer elements and stabilizes NANOG binding to chromatin in ground-state embryonic stem cells, particularly at genes encoding enzymes of choline/one-carbon metabolism (Bhmt, Bhmt2, Dmgdh). SPIC controls the SAM-to-SAH flux, thereby modulating H3R17me2 and H3K4me3 histone methylation marks. Gain- and loss-of-function in ESCs, ChIP analysis, metabolic flux measurement (SAM/SAH), histone modification assay Science advances Medium 37595034
2023 In zebrafish, the ETS transcription factor Spic guides in situ generation of metaphocytes (tissue-resident macrophage/DC-like cells of non-hematopoietic origin) from local progenitors; Spic deficiency results in absence of metaphocytes. Metaphocytes are the major IL-22BP-producing cells, and their depletion causes dysregulated barrier immunity. Zebrafish spic knockout, lineage tracing, cell depletion, IL-22BP expression assay Cell reports Medium 37148242
2026 Silencing of the m6A writer Zc3h13 stabilizes Spic mRNA in an m6A-dependent manner, thereby increasing SPIC protein levels, inhibiting NF-κB pathway activation, and attenuating LPS-induced inflammatory responses in macrophages. Co-silencing of Spic reverses the anti-inflammatory effects of Zc3h13 knockdown. siRNA knockdown of Zc3h13 and Spic in macrophages, m6A methylation assay, mRNA stability assay, NF-κB pathway analysis, in vivo mouse LPS model Journal of immunology Medium 41847860

Source papers

Stage 0 corpus · 41 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis. Nature 360 19037245
2014 Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages. Cell 337 24630724
2019 Inflammation induces stress erythropoiesis through heme-dependent activation of SPI-C. Science signaling 68 31506384
2002 SpiC is required for secretion of Salmonella Pathogenicity Island 2 type III secretion system proteins. Cellular microbiology 64 12174087
2003 The Salmonella SpiC protein targets the mammalian Hook3 protein function to alter cellular trafficking. Molecular microbiology 52 12950921
2002 Identification of a NIPSNAP homologue as host cell target for Salmonella virulence protein SpiC. Cellular microbiology 52 12427096
2004 SsaM and SpiC interact and regulate secretion of Salmonella pathogenicity island 2 type III secretion system effectors and translocators. Molecular microbiology 49 15491354
2020 Counter Regulation of Spic by NF-κB and STAT Signaling Controls Inflammation and Iron Metabolism in Macrophages. Cell reports 47 32610126
1999 Spi-C, a novel Ets protein that is temporally regulated during B lymphocyte development. The Journal of biological chemistry 40 10187812
2010 Regulation of follicular B cell differentiation by the related E26 transformation-specific transcription factors PU.1, Spi-B, and Spi-C. Journal of immunology (Baltimore, Md. : 1950) 36 21057087
2003 Construction, characterization, and immunogenicity of an attenuated Salmonella enterica serovar typhimurium pgtE vaccine expressing fimbriae with integrated viral epitopes from the spiC promoter. Infection and immunity 32 12874347
2020 WbaP is required for swarm motility and intramacrophage multiplication of Salmonella Enteritidis spiC mutant by glucose use ability. Microbiological research 19 33429286
2019 RAG-Mediated DNA Breaks Attenuate PU.1 Activity in Early B Cells through Activation of a SPIC-BCLAF1 Complex. Cell reports 17 31644907
2008 Salmonella virulence factor SpiC is involved in expression of flagellin protein and mediates activation of the signal transduction pathways in macrophages. Microbiology (Reading, England) 17 18957602
2023 Spic regulates one-carbon metabolism and histone methylation in ground-state pluripotency. Science advances 16 37595034
2021 Safety and protective efficacy of Salmonella Pullorum spiC and rfaH deletion rough mutant as a live attenuated DIVA vaccine candidate. Poultry science 16 34991038
2020 Opposing Roles for the Related ETS-Family Transcription Factors Spi-B and Spi-C in Regulating B Cell Differentiation and Function. Frontiers in immunology 15 32457757
2003 SPI-C, a PU-box binding ETS protein expressed temporarily during B-cell development and in macrophages, contains an acidic transactivation domain located to the N-terminus. Molecular immunology 14 12749910
1998 Long-term survival effect of metoprolol in dilated cardiomyopathy. The SPIC (Italian Multicentre Cardiomyopathy Study) Group. Heart (British Cardiac Society) 14 9616339
2021 Salmonella Pullorum spiC mutant is a desirable LASV candidate with proper virulence, high immune protection and easy-to-use oral administration. Vaccine 12 33551301
2002 Genomic structure of mouse SPI-C and genomic structure and expression pattern of human SPI-C. Gene 12 12459275
2019 Evaluation of the Safety and Protection Efficacy of spiC and nmpC or rfaL Deletion Mutants of Salmonella Enteritidis as Live Vaccine Candidates for Poultry Non-Typhoidal Salmonellosis. Vaccines 11 31801257
2008 Transgenic expression of Spi-C impairs B-cell development and function by affecting genes associated with BCR signaling. European journal of immunology 11 18792411
2015 Identification of a negative regulatory role for spi-C in the murine B cell lineage. Journal of immunology (Baltimore, Md. : 1950) 10 25769919
2013 SPIC: a novel similarity metric for comparing transcription factor binding site motifs based on information contents. BMC systems biology 10 24564945
2009 Involvement of SPI-2-encoded SpiC in flagellum synthesis in Salmonella enterica serovar Typhimurium. BMC microbiology 8 19706157
2006 SPI-C and STAT6 can cooperate to stimulate IgE germline transcription. Biochemical and biophysical research communications 8 16647686
1995 [Dilated cardiomyopathy: a new natural history? The experience of the Italian Multicenter Cardiomyopathy Study (SPIC)]. Giornale italiano di cardiologia 8 8529848
2020 Spi-C positively regulates RANKL-mediated osteoclast differentiation and function. Experimental & molecular medicine 7 32341419
2021 Evaluation of Safety and Protective Efficacy of a waaJ and spiC Double Deletion Korean Epidemic Strain of Salmonella enterica Serovar Gallinarum. Frontiers in veterinary science 6 34869728
2019 Controversy Surrounding the Function of SpiC Protein in Salmonella: An Overview. Frontiers in microbiology 6 31440219
2023 Metaphocytes are IL-22BP-producing cells regulated by ETS transcription factor Spic and essential for zebrafish barrier immunity. Cell reports 5 37148242
2022 The E26 Transformation-Specific Family Transcription Factor Spi-C Is Dynamically Regulated by External Signals in B Cells. ImmunoHorizons 3 38285436
2015 Preparation of Monoclonal Antibodies Against SpiC Protein Secreted by T3SS-2 of Salmonella spp. Monoclonal antibodies in immunodiagnosis and immunotherapy 3 26683183
2021 Lineage-instructive functions of the E26-transformation-specific-family transcription factor Spi-C in immune cell development and disease. WIREs mechanisms of disease 2 34730294
2025 Burn injury-induced G-CSF secretion reduces spic+ erythroblastic island macrophages in the bone marrow and impairs medullary erythropoiesis. Journal of immunology (Baltimore, Md. : 1950) 1 40073238
2024 Salmonella enterica serovar typhimurium effectors spiA and spiC promote replication by modulating iron metabolism and oxidative stress. Veterinary microbiology 1 39674031
2023 Spi-C and PU.1 Counterregulate Rag1 and Igκ Transcription to Effect Vκ-Jκ Recombination in Small Pre-B Cells. Journal of immunology (Baltimore, Md. : 1950) 1 37195219
2015 [Prokaryotic expression and application of SpiC protein of Salmonella pullorum]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 1 25652851
2026 The Emerging Role of Transcription Factor Spi-C in Macrophage Biology and Inflammatory Pathogenesis. International journal of molecular sciences 0 41751866
2026 Silencing of Zc3h13 attenuates LPS-induced inflammatory response in macrophages via m6A-dependent stabilization of Spic mRNA. Journal of immunology (Baltimore, Md. : 1950) 0 41847860