Butyrophilin subfamily 3 member A3 (BTN3A3, also known as BTF3) is a type I transmembrane protein belonging to the extended B7 family of immune regulatory molecules. It contains two extracellular immunoglobulin domains and an intracellular B30.2 (PRYSPRY) domain. BTN3A3 plays a role in T cell-mediated immunity, particularly in the regulation of Vgamma9Vdelta2 T cells, though it is less functionally active than its close paralog BTN3A1. The protein forms homodimers and can heterodimerize with BTN3A1, regulating immune responses and potentially contributing to cancer biology.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001817 regulation of cytokine production | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA annotation for regulation of cytokine production. This is a general biological process annotation that may apply more to BTN3A1 than BTN3A3. The deep research suggests BTN3A3 has roles in immune regulation but does not provide specific evidence that BTN3A3 directly regulates cytokine production. Reason: While BTN3A3 is involved in immune responses and T cell-mediated immunity, the specific evidence for regulation of cytokine production is limited for BTN3A3 specifically. This annotation likely derives from phylogenetic inference based on BTN3A1, which has more direct experimental evidence for this function. BTN3A3 appears to have a supporting rather than primary role in T cell activation, which may indirectly affect cytokine production. Marking as non-core pending more specific experimental evidence. Supporting Evidence: file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md BTN3A3 functions as a signaling receptor and is involved in immune regulation, particularly in T-cell responses. Its molecular functions include: Signaling receptor binding, Regulation of cytokine production, T cell-mediated immunity |
| GO:0005102 signaling receptor binding | IBA GO_REF:0000033 | MODIFY | Summary: IBA annotation for signaling receptor binding. BTN3A3 can bind to other BTN3A family members and potentially to receptors on T cells, consistent with its role in immune signaling. Reason: The term "signaling receptor binding" (GO:0005102) is too vague and does not capture the specific molecular function of BTN3A3. The protein has more specific functions related to immune receptor activity and protein heterodimerization. BTN3A3 acts as an immune regulatory molecule that can interact with BTN3A1 and BTN3A2 through its IgC domain to form heterodimers. A more informative term would be immune receptor activity or protein heterodimerization activity. Proposed replacements: immune receptor activity protein heterodimerization activity Supporting Evidence: PMID:29339503 BTN3A3 could also be coimmunoprecipitated with BTN3A1 (Fig. S3A), consistent with its potential to functionally collaborate with BTN3A1 in the absence of BTN3A2 (Fig. 1D). |
| GO:0009897 external side of plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for external side of plasma membrane. BTN3A3 is a type I transmembrane protein with extracellular immunoglobulin domains that face the external side of the membrane. Reason: This annotation is correct and well-supported. BTN3A3 is a type I transmembrane protein with two extracellular Ig domains (IgV and IgC) that extend to the external side of the plasma membrane. UniProt confirms this topology with extracellular domain from residues 30-248. This is consistent with its function as an immune regulatory molecule that interacts with other cell surface proteins and potentially with T cell receptors. Supporting Evidence: file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md BTN3A3 is a type I membrane protein, meaning it is anchored in the plasma membrane with its N-terminus extracellular and C-terminus intracellular |
| GO:0050852 T cell receptor signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA annotation for T cell receptor signaling pathway. BTN3A3 has been shown to play a role in T cell responses, though the experimental evidence is stronger for BTN3A1. Reason: BTN3A3 is involved in T cell-mediated immunity and can modulate T cell responses, but the primary functional molecule in this pathway is BTN3A1. BTN3A3 appears to play a supporting role, potentially through heterodimerization with BTN3A1. PMID:22767497 demonstrated the key role of CD277/BTN3A in T cell responses, but focused primarily on the BTN3A1 isoform for PAg sensing. BTN3A3 may contribute to TCR signaling indirectly through its interactions with BTN3A1. Supporting Evidence: PMID:22767497 VΞ³9VΞ΄2 T-cell activation by agonist anti-CD277 mAbs was restored after re-expression of any of the 3 CD277 isoforms, responses to PAg or NBP were obtained after re-expression of BTN3A1 only. file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md T cell receptor signaling pathway |
| GO:0002250 adaptive immune response | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation based on UniProtKB keyword mapping for adaptive immune response. This is appropriately general for BTN3A3 role in immunity. Reason: This annotation is correct at an appropriate level of generality. BTN3A3 plays a role in adaptive immunity through its involvement in T cell-mediated immune responses. As a member of the butyrophilin family within the extended B7 superfamily, it contributes to immune regulation. The annotation is supported by UniProt function annotation stating it plays a role in T-cell responses in the adaptive immune response. Supporting Evidence: file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md Adaptive immune response |
| GO:0002376 immune system process | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation for immune system process. This is a very general parent term that is clearly correct for BTN3A3. Reason: This is an appropriately general annotation for BTN3A3, which is clearly involved in immune system processes through its role in T cell regulation and adaptive immunity. While this term is very broad, it accurately captures the biological context of BTN3A3 function. The term is a parent of more specific terms like adaptive immune response and T cell mediated immunity. Supporting Evidence: file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md BTN3A3 is involved in several critical biological processes: T cell-mediated immunity, Regulation of cytokine production, Immune response modulation |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProtKB subcellular location mapping. BTN3A3 is correctly annotated to plasma membrane. Reason: This annotation is correct. BTN3A3 is a type I transmembrane protein that localizes to the plasma membrane as confirmed by UniProt and multiple experimental studies. The protein has a signal peptide (residues 1-29), extracellular domain (30-248), transmembrane helix (249-269), and cytoplasmic domain (270-584). Cell membrane localization was confirmed experimentally by PMID:22767497. Supporting Evidence: file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md Plasma membrane |
| GO:0005515 protein binding | IPI PMID:29339503 Heteromeric interactions regulate butyrophilin (BTN) and BTN... | MODIFY | Summary: IPI annotation for protein binding based on BTN3A1 interaction. This term is too vague per curation guidelines. Reason: While the evidence from PMID:29339503 clearly demonstrates that BTN3A3 binds to BTN3A1, the term "protein binding" (GO:0005515) is explicitly discouraged in the curation guidelines as it does not provide informative functional information. The specific interaction demonstrated is protein heterodimerization, which is a more informative molecular function term. BTN3A3 forms heterodimers with BTN3A1 to regulate immune responses. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:29339503 BTN3A3 could also be coimmunoprecipitated with BTN3A1 (Fig. S3A), consistent with its potential to functionally collaborate with BTN3A1 in the absence of BTN3A2 (Fig. 1D). |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: IPI annotation for protein binding from a proteome-scale interactome study. This term is too vague per curation guidelines. Reason: PMID:33961781 is a large-scale proteomics study mapping cell-specific protein-protein interactions. While it likely identified BTN3A3 interactions, the generic term "protein binding" does not provide useful functional information per curation guidelines. Without access to the specific interaction partners identified in this study, and given that we have better characterized interactions with BTN3A1 from PMID:29339503, this annotation should be replaced with the more specific protein heterodimerization activity term. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:33961781 Thousands of interactions assemble proteins into modules that impart spatial and functional organization to the cellular proteome |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8851038 | ACCEPT | Summary: TAS annotation from Reactome pathway for BTN3A1 binding prenylated phosphoantigens. This pathway primarily describes BTN3A1, not BTN3A3. Reason: While the Reactome pathway R-HSA-8851038 focuses on BTN3A1 binding to prenylated phosphoantigens, BTN3A3 is also a plasma membrane protein as established by multiple lines of evidence. The localization annotation is correct even if the specific Reactome pathway is more relevant to BTN3A1. BTN3A3 is present at the plasma membrane as a type I transmembrane protein. Supporting Evidence: file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md Plasma membrane |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | ACCEPT | Summary: HDA annotation from high-throughput detection study of NK cell membrane proteome. This is a very general parent term. Reason: PMID:19946888 is a proteomics study defining the membrane proteome of NK cells, which detected BTN3A3. The annotation to the general term "membrane" (GO:0016020) is correct, though less specific than plasma membrane. BTN3A3 is indeed an integral membrane protein. This annotation can coexist with the more specific plasma membrane annotations. Supporting Evidence: file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md Integral component of the membrane PMID:19946888 The present study was initiated to define the composition of the membrane proteome of the Natural Killer (NK) like cell line YTS |
| GO:0002456 T cell mediated immunity | IMP PMID:22767497 Key implication of CD277/butyrophilin-3 (BTN3A) in cellular ... | ACCEPT | Summary: IMP annotation for T cell mediated immunity from key experimental study. This is a core function, though primarily demonstrated for BTN3A1. Reason: PMID:22767497 is the key study demonstrating the role of CD277/BTN3A molecules in VΞ³9VΞ΄2 T cell activation by phosphoantigens. The study showed that CD277 knockdown and domain-shuffling approaches confirmed the implication of BTN3A1 in PAg sensing, and that antibody 20.1 against CD277 (which recognizes all three BTN3A isoforms) can activate T cells. While BTN3A1 is the primary functional isoform, BTN3A3 contributes to T cell-mediated immunity through its expression and potential collaborative functions with BTN3A1. The IMP evidence code indicates this was demonstrated by mutant phenotype analysis. Supporting Evidence: PMID:22767497 This study demonstrates a novel role played by B7-like molecules in human Ξ³Ξ΄ T-cell antigenic activation file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md T cell-mediated immunity |
| GO:0005886 plasma membrane | IDA PMID:22767497 Key implication of CD277/butyrophilin-3 (BTN3A) in cellular ... | ACCEPT | Summary: IDA annotation for plasma membrane with direct experimental evidence from PMID:22767497. Reason: PMID:22767497 provides direct experimental evidence (IDA) for plasma membrane localization of BTN3A proteins including BTN3A3. The study included confocal microscopy and flow cytometry demonstrating cell surface expression. UniProt also confirms that BTN3A3 subcellular location was determined in this study. This is strong experimental evidence for plasma membrane localization. Supporting Evidence: file:human/BTN3A3/BTN3A3-deep-research-perplexity-lite.md Plasma membrane PMID:22767497 We show that treatment of nonsusceptible target cells with antibody 20.1 against CD277, a member of the extended B7 superfamily related to butyrophilin, mimics PAg-induced VΞ³9VΞ΄2 T-cell activation |
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