Affinage

SEMA4A

Semaphorin-4A · UniProt Q9H3S1

Length
761 aa
Mass
83.6 kDa
Annotated
2026-06-10
24 papers in source corpus 12 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SEMA4A is a class IV transmembrane semaphorin that operates bidirectionally as both a ligand and a reverse-signaling receptor to regulate immune cell differentiation, neuronal guidance, and tissue homeostasis (PMID:12374982, PMID:20043131, PMID:28007914). In the immune system it acts as a costimulatory ligand required for T cell priming and Th1/Th17 differentiation, with dendritic-cell-derived SEMA4A driving priming and T-cell-derived SEMA4A sustaining Th1 responses through T-bet expression (PMID:15780988); it was first defined through the receptor Tim-2 on activated T cells (PMID:12374982), and is released from dendritic cells by metalloproteinase-dependent shedding (PMID:22491253). On CD8+ T cells SEMA4A engages Plexin-B2 to activate mTORC1 (while restraining mTORC2), driving effector cytokine production, a role that places it downstream of IL-33 in antitumor CD8+ responses (PMID:26116513, PMID:34380650). SEMA4A also inhibits Th2 responses through a Tim-2-independent mechanism (PMID:23007237) and, on hematopoietic cells, accelerates Th17-mediated neuroinflammation (PMID:32169103). As a guidance ligand, SEMA4A binds Plexin-B1/B2/B3 to induce neuronal growth cone collapse via the Rho-family GTPase Rnd1 and downregulation of R-Ras (PMID:20043131). Reciprocally, SEMA4A itself transduces reverse signals upon Plexin-B1 binding, recruiting the polarity protein Scrib away from the Rac/Cdc42 exchange factor βPIX to lower Rac1/Cdc42 activity and regulate cell migration (PMID:28007914). Through Plexin-B2 it additionally protects skeletal muscle by suppressing FoxO3a nuclear translocation and reactivating PI3K-AKT-mTOR anabolic signaling (PMID:42216457). Disease-associated mutations (D345H, F350C) cause ER retention that renders retinal pigment epithelial cells susceptible to oxidative and ER stress (PMID:22956603).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2002 High

    Establishing that SEMA4A is an immune ligand rather than solely a neuronal molecule, this work showed it enhances T-cell activation and identified its first receptor.

    Evidence Expression cloning identifying Tim-2, in vitro/in vivo T-cell activation with blocking antibodies

    PMID:12374982

    Open questions at the time
    • Did not establish downstream signaling from Tim-2
    • Did not address other receptors used by SEMA4A
  2. 2005 High

    Genetic loss-of-function defined SEMA4A as a costimulatory signal partitioned by cell source, with DC-derived protein driving priming and T-cell-derived protein driving Th1 polarization.

    Evidence Sema4A knockout mice, cell-type-specific DC reconstitution, in vitro Th differentiation

    PMID:15780988

    Open questions at the time
    • Receptor on responding T cells for Th1 effect not defined
    • Molecular signaling linking SEMA4A to T-bet not resolved
  3. 2010 High

    This work mapped SEMA4A's neuronal guidance activity to B-type plexins and a defined intracellular GTPase cascade.

    Evidence Transfection binding assays, COS-7 contraction and hippocampal growth cone collapse, constitutively active R-Ras rescue

    PMID:20043131

    Open questions at the time
    • Did not distinguish contributions of individual B-type plexins in vivo
    • Link between Rnd1 and R-Ras suppression not biochemically detailed
  4. 2012 Medium

    Disease mutations were shown to impair SEMA4A trafficking, connecting altered subcellular localization to stress susceptibility in retinal cells.

    Evidence Confocal localization of D345H/F350C mutants, ER/oxidative stress and phagocytosis assays in ARPE-19 cells, zebrafish ER stress model

    PMID:22956603

    Open questions at the time
    • Did not establish patient-level causation in a family study
    • Mechanism by which ER retention triggers stress susceptibility not detailed
  5. 2012 Medium

    Two studies extended SEMA4A's immune role, showing metalloproteinase-dependent shedding generates a soluble form and that SEMA4A suppresses Th2 responses partly independent of Tim-2.

    Evidence Metalloproteinase inhibitor experiments and Th1/Th17 assays; Sema4A-Fc administration and Tim-2-deficient mice in an asthma model

    PMID:22491253 PMID:23007237

    Open questions at the time
    • The non-Tim-2 receptor mediating Th2 inhibition was not identified
    • Protease responsible for shedding not named
  6. 2014 Medium

    A germline SEMA4A mutation was linked to enhanced proliferative signaling, implicating SEMA4A variation in cancer cell behavior.

    Evidence Reconstitution of WT vs V78M SEMA4A in deficient HCT-116 cells, MAPK/Erk and PI3K/Akt assays, cell cycle analysis

    PMID:25307848

    Open questions at the time
    • Receptor and mechanism driving mutant gain-of-signaling not defined
    • In vivo tumorigenic relevance not established
  7. 2015 High

    This study identified Plexin-B2 as the functional CD8+ T cell receptor and placed SEMA4A upstream of mTORC1 in driving effector differentiation.

    Evidence Sema4A knockout mice, Listeria infection, mTORC1/mTORC2 assays, recombinant Sema4A rescue, receptor identification

    PMID:26116513

    Open questions at the time
    • How Plexin-B2 engagement biases mTORC1 over mTORC2 not resolved
    • Intracellular adaptors linking receptor to mTOR not identified
  8. 2016 High

    Reverse signaling was established: SEMA4A acts as a receptor when bound by Plexin-B1, recruiting Scrib to suppress Rac1/Cdc42 and control migration.

    Evidence Mass spectrometry, siRNA screen, Co-IP, Rac1/Cdc42 activity and migration assays in cancer cells and DCs

    PMID:28007914

    Open questions at the time
    • Intracellular motif of SEMA4A mediating Scrib recruitment not mapped
    • Physiological contexts of reverse signaling in vivo not delineated
  9. 2020 Medium

    Cell-source dissection showed hematopoietic SEMA4A specifically promotes the effector phase of Th17-mediated neuroinflammation.

    Evidence Adoptive transfer EAE with Sema4A knockout recipients and bone marrow chimeras

    PMID:32169103

    Open questions at the time
    • Specific hematopoietic cell type providing SEMA4A not pinpointed
    • Receptor mediating the Th17 effector effect not defined
  10. 2021 Medium

    SEMA4A was placed downstream of IL-33 as an intrinsic requirement for IL-33-driven antitumor CD8+ T cell responses.

    Evidence Syngeneic tumor models, Sema4A knockout mice, IL-33 administration, tumor-infiltrating CD8+ IFN-γ assays

    PMID:34380650

    Open questions at the time
    • Mechanism of IL-33 induction of SEMA4A on DCs not detailed
    • Direct DC-to-CD8 SEMA4A signaling in vivo not visualized
  11. 2024 Medium

    A new ligand-receptor axis emerged: neutrophil-derived SEMA4A signals via Plexin-D1 to protect myeloid-biased HSC epigenetic state and inflammatory resilience.

    Evidence Sema4A knockout mice, bone marrow reconstitution, epigenetic profiling, HSC functional assays, Plexin-D1 identification (preprint)

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Mechanism linking Plexin-D1 to epigenetic maintenance not detailed
  12. 2025 Medium

    SEMA4A was shown to act through Plexin-B2 in muscle to block atrophy and promote anabolism, defining a non-immune tissue-protective role.

    Evidence AAV Sema4A overexpression, dexamethasone atrophy and injury models, C2C12 gain/loss-of-function, FoxO3a and PI3K-AKT-mTOR analyses

    PMID:42216457

    Open questions at the time
    • Source of physiological SEMA4A acting on muscle not established
    • How one ligand-receptor pair coordinates FoxO3a suppression and PI3K-AKT-mTOR activation not detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single semaphorin selects among multiple receptors (Tim-2, Plexin-B1/B2/B3, Plexin-D1) and switches between forward-ligand and reverse-receptor modes across tissues remains unresolved.
  • No unified model for receptor selection across cell types
  • Structural basis of bidirectional signaling not defined
  • Role of shedding in tuning ligand vs membrane signaling unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 2 GO:0060089 molecular transducer activity 1
Localization
GO:0005886 plasma membrane 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 1
Partners
PLXNB1PLXNB2PLXNB3PLXND1RND1SCRIBTIMD2

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Sema4A, expressed on dendritic cells and B cells, enhances T-cell activation and differentiation in vitro and in vivo; expression cloning identified Tim-2 (a T-cell immunoglobulin and mucin domain protein expressed on activated T cells) as the Sema4A receptor. Expression cloning, in vitro T-cell activation assays, in vivo immunization, monoclonal antibody blocking experiments Nature High 12374982
2005 Sema4A provides a costimulatory signal required for T cell priming and Th1 differentiation; DC-derived Sema4A is important for T cell priming while T cell-derived Sema4A (upregulated on Th1-differentiating cells) is required for Th1 responses and T-bet expression. Loss of Sema4A impairs allostimulatory activity of DCs and Th differentiation. Sema4A knockout mice, bone marrow reconstitution with antigen-pulsed DCs, in vitro Th differentiation assays, in vivo antigen-specific T cell priming Immunity High 15780988
2010 Sema4A binds Plexin-B1, -B2, and -B3 and induces growth cone collapse in hippocampal neurons through B-type plexin-mediated signaling; the intracellular signal is transmitted through Rnd1 (a Rho family GTPase), and Sema4A-induced growth cone collapse is blocked by constitutively active R-Ras, indicating that Sema4A acts by down-regulating R-Ras activity. Transfection of COS-7 cells with plexin/Rnd1 expression vectors, COS-7 cell contraction assay, hippocampal neuron growth cone collapse assay, dominant-active R-Ras rescue experiment International journal of molecular medicine High 20043131
2012 Sema4A mutants D345H and F350C mis-localize to the ER instead of the plasma membrane, rendering retinal pigment epithelial cells susceptible to light irradiation, oxidative stress, and ER stress, and suppressing phagocytosis; in zebrafish, human mutant SEMA4A increased ER stress marker ddit3 mRNA under ER stress conditions. Confocal microscopy for intracellular localization, overexpression of mutant vs. wild-type SEMA4A in ARPE-19 cells, GRP78 expression assay, phagocytosis assay, tunicamycin and H2O2 cell death assays, zebrafish ER stress model Investigative ophthalmology & visual science Medium 22956603
2012 Sema4A is shed from DCs in a metalloproteinase-dependent manner; DC-derived Sema4A promotes both Th1 and Th17 cell differentiation. Serum Sema4A measurement, DC surface expression analysis, metalloproteinase inhibitor experiments, Th1/Th17 differentiation assays in MS patients and controls Journal of immunology Medium 22491253
2012 Sema4A inhibits Th2-type immune responses; Sema4A-Fc directly inhibits IL-4-producing OVA-specific CD4+ T cells and ameliorates airway hyperreactivity and lung inflammation in an asthma model, with inhibitory effects observed even in Tim-2-deficient mice, indicating the inhibitory effect on Th2 is not solely through Tim-2. Sema4A knockout mice on BALB/c background, in vivo OVA-sensitization/challenge asthma model, systemic Sema4A-Fc administration, Tim-2-deficient mice, in vitro T cell cytokine assays Journal of clinical immunology Medium 23007237
2014 SEMA4A germline mutation V78M leads to significantly increased MAPK/Erk and PI3K/Akt signaling as well as enhanced cell cycle progression compared to wild-type SEMA4A when expressed in SEMA4A-deficient HCT-116 colorectal cancer cells. Re-expression of wild-type vs. V78M SEMA4A in SEMA4A-deficient HCT-116 cells, MAPK/Erk and PI3K/Akt signaling assays, cell cycle analysis Nature communications Medium 25307848
2015 SEMA4A regulates CD8+ T cell activation and differentiation by activating mTORC1; SEMA4A-deficient CD8+ T cells show reduced mTORC1 activity and elevated mTORC2 activity, impaired IFN-γ/TNF-α production, and reduced effector molecule expression. Plexin-B2 was identified as the functional SEMA4A receptor on CD8+ T cells. Recombinant Sema4A protein restored IFN-γ production and mTORC1 activity in SEMA4A-deficient CD8+ T cells. SEMA4A knockout mice, Listeria monocytogenes infection model, mTORC1/mTORC2 activity assays, cytokine measurement, recombinant Sema4A rescue experiment, receptor identification Journal of immunology High 26116513
2016 Sema4A functions as a receptor (not only a ligand) and transduces reverse signals triggered by Plexin-B1 binding; this reverse signaling promotes interaction of Sema4A with the polarity protein Scrib, displacing Scrib from its complex with the Rac/Cdc42 exchange factor βPIX, thereby decreasing Rac1 and Cdc42 GTPase activity and regulating cell migration in cancer cells and dendritic cells. Mass spectrometry, siRNA screening, Co-IP/pulldown for Sema4A–Scrib interaction, Rac1/Cdc42 activity assays, cell migration assays in cancer cells and DCs The Journal of cell biology High 28007914
2020 Sema4A expressed on hematopoietic cells (not CNS-resident cells) accelerates Th17 cell-mediated neuroinflammation in the effector phase; adoptive transfer of Th17-skewed encephalitogenic T cells into Sema4A-deficient recipients showed significantly reduced disease severity, while Th1-skewed transfer showed no difference. Adoptive transfer EAE model, Sema4A knockout recipient mice, bone marrow chimera experiments, clinical scoring and CNS cellular infiltration analysis Journal of neuroinflammation Medium 32169103
2021 IL-33 induces dendritic cells to express Sema4A, and Sema4A is intrinsically required for the antitumor effects of IL-33; absence of Sema4A abolished IL-33-mediated tumor growth inhibition and IFN-γ upregulation by tumor-infiltrating CD8+ T cells. Syngeneic mouse tumor models, Sema4A knockout mice, IL-33 administration, tumor growth measurement, IFN-γ production assay by tumor-infiltrating CD8+ T cells Journal of immunology Medium 34380650
2024 Sema4A, produced mainly by neutrophils, signals via Plexin D1 on myeloid-biased hematopoietic stem cells (myHSC) to safeguard their epigenetic state and confer resilience to inflammatory stress; absence of Sema4A leads to myHSC inflammatory hyper-responsiveness, excessive myHSC expansion, myeloid bias, and profound loss of regenerative function with age. Sema4A knockout mice, bone marrow reconstitution, epigenetic profiling, HSC subset functional assays, cell-surface receptor identification (Plexin D1) bioRxiv (preprint)preprint Medium
2025 In skeletal muscle, Sema4A signals through Plexin-B2 to suppress FoxO3a nuclear translocation and inhibit atrogene expression while simultaneously reactivating the PI3K-AKT-mTOR anabolic pathway; AAV-mediated Sema4A restoration attenuates dexamethasone-induced muscle atrophy and accelerates injury recovery in mice. AAV-mediated Sema4A overexpression, dexamethasone-induced atrophy model, acute injury model, C2C12 myotube gain/loss-of-function, FoxO3a nuclear translocation assay, PI3K-AKT-mTOR pathway analysis Journal of cachexia, sarcopenia and muscle Medium 42216457

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Class IV semaphorin Sema4A enhances T-cell activation and interacts with Tim-2. Nature 269 12374982
2005 Nonredundant roles of Sema4A in the immune system: defective T cell priming and Th1/Th2 regulation in Sema4A-deficient mice. Immunity 136 15780988
2005 Identification of novel mutations in the SEMA4A gene associated with retinal degenerative diseases. Journal of medical genetics 63 16199541
2014 Germline variants in the SEMA4A gene predispose to familial colorectal cancer type X. Nature communications 53 25307848
2012 Elevation of Sema4A implicates Th cell skewing and the efficacy of IFN-β therapy in multiple sclerosis. Journal of immunology (Baltimore, Md. : 1950) 46 22491253
2016 The role of Sema4A in angiogenesis, immune responses, carcinogenesis, and retinal systems. Cell adhesion & migration 44 27736304
2015 mTOR Complex Signaling through the SEMA4A-Plexin B2 Axis Is Required for Optimal Activation and Differentiation of CD8+ T Cells. Journal of immunology (Baltimore, Md. : 1950) 38 26116513
2010 Sema4A induces cell morphological changes through B-type plexin-mediated signaling. International journal of molecular medicine 38 20043131
2016 A reverse signaling pathway downstream of Sema4A controls cell migration via Scrib. The Journal of cell biology 32 28007914
2022 Unbiased cell surface proteomics identifies SEMA4A as an effective immunotherapy target for myeloma. Blood 30 35134130
2012 An inhibitory role for Sema4A in antigen-specific allergic asthma. Journal of clinical immunology 26 23007237
2012 SEMA4A mutations lead to susceptibility to light irradiation, oxidative stress, and ER stress in retinal pigment epithelial cells. Investigative ophthalmology & visual science 16 22956603
2018 Sema4A Responds to Hypoxia and Is Involved in Breast Cancer Progression. Biological & pharmaceutical bulletin 15 30270262
2021 IL-33 Induces Sema4A Expression in Dendritic Cells and Exerts Antitumor Immunity. Journal of immunology (Baltimore, Md. : 1950) 14 34380650
2020 Sema4A is implicated in the acceleration of Th17 cell-mediated neuroinflammation in the effector phase. Journal of neuroinflammation 13 32169103
2023 Design of a potential Sema4A-based multi-epitope vaccine to combat triple-negative breast cancer: an immunoinformatic approach. Medical oncology (Northwood, London, England) 12 36823384
2022 The possible involvement of sema3A and sema4A in the pathogenesis of multiple sclerosis. Clinical immunology (Orlando, Fla.) 4 35460904
2017 On variants and disease-causing mutations: Case studies of a SEMA4A variant identified in inherited blindness. Ophthalmic genetics 3 28805479
2025 Developing SEMA4A-directed CAR T cells to overcome low BCMA antigen density in multiple myeloma. Cancer cell 2 41072416
2019 T-cell specific upregulation of Sema4A as risk factor for autoimmunity in systemic lupus erythematosus and rheumatoid arthritis. Autoimmunity 2 31876207
2014 [Sema4A as a biomarker predicting responsiveness to IFN β treatment]. Rinsho shinkeigaku = Clinical neurology 1 25519959
2026 Sema4A Protects Against Muscle Atrophy and Promotes Repair by Regulating Intracellular Metabolic Signalling. Journal of cachexia, sarcopenia and muscle 0 42216457
2025 Deciphering the role of SEMA4A/MAPK signaling in sepsis: insights from Mendelian randomization, transcriptomic, single-cell sequencing analyses, and vitro experiments. Frontiers in cellular and infection microbiology 0 40756031
2024 A Pilot Study of the Role of Semaphorin 4A (sema4A) and 3C (sema3C) in Non-Muscle-Invasive Bladder Cancer (NMIBC). Biomedicines 0 39457718

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