IL4I1 (Interleukin-4-induced gene 1) encodes a secreted L-amino-acid oxidase (LAAO) belonging to the flavin monoamine oxidase family. The enzyme catalyzes oxidative deamination of L-amino acids to alpha-keto acids with concomitant production of hydrogen peroxide and ammonia. IL4I1 preferentially acts on aromatic amino acids (Phe > Tyr > Trp) and has weak activity on L-arginine. Through tryptophan catabolism, IL4I1 generates indole-3-pyruvic acid (I3P) which gives rise to indole metabolites (IAA, I3A) and kynurenic acid that activate the aryl hydrocarbon receptor (AHR). IL4I1 functions as a metabolic immune checkpoint, suppressing T cell activation and proliferation, promoting FoxP3+ Treg differentiation, and facilitating tumor immune evasion. It is secreted at the immunological synapse and expressed primarily by antigen-presenting cells including dendritic cells, macrophages, and B cells. IL4I1 is also present in spermatozoa where it localizes to the acrosomal vesicle and midpiece and may regulate capacitation and acrosomal exocytosis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0009063 amino acid catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: IL4I1 is confirmed as an L-amino-acid oxidase that catalyzes catabolism of aromatic amino acids (phenylalanine, tyrosine, tryptophan) to their respective alpha-keto acids [PMID:17356132, PMID:32818467, PMID:32866000]. This term is appropriately broad as IL4I1 does catabolize amino acids as its core enzymatic function. Reason: The IBA annotation for amino acid catabolic process is appropriate and supported by extensive experimental evidence. IL4I1 has been demonstrated to oxidize aromatic amino acids (Phe, Tyr, Trp) to their alpha-keto acid products, which constitutes amino acid catabolism. More specific annotations (GO:0006559, GO:0006569, GO:0006572) are also present with IDA evidence, so this broader IBA term is retained as phylogenetically inferred and consistent with core function. Supporting Evidence: PMID:17356132 We showed that IL4I1 has l-amino acid oxidase activity, optimal at physiological pH and primarily directed toward phenylalanine. PMID:32818467 IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid. file:human/IL4I1/IL4I1-deep-research-falcon.md See deep research file for comprehensive analysis |
| GO:0001716 L-amino-acid oxidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: L-amino-acid oxidase activity is the core molecular function of IL4I1. Phylogenetic inference by IBA is strongly supported by multiple IDA annotations in this same review [PMID:17356132, PMID:25767141, PMID:26673964, PMID:32818467, PMID:32866000]. Reason: This phylogenetically inferred annotation represents the core molecular function of IL4I1. Multiple IDA annotations with experimental evidence support this activity, making this IBA annotation redundant but appropriately consistent. Supporting Evidence: PMID:17356132 We showed that IL4I1 has l-amino acid oxidase activity, optimal at physiological pH and primarily directed toward phenylalanine. |
| GO:0001669 acrosomal vesicle | IEA GO_REF:0000044 | ACCEPT | Summary: This IEA annotation based on UniProt subcellular location is supported by experimental IDA evidence from PMID:25767141 demonstrating IL4I1 localization to the acrosomal region in human spermatozoa. Reason: The electronic annotation is correct and consistent with experimental evidence. IDA annotations for the same term from PMID:25767141 provide direct support. Supporting Evidence: PMID:25767141 the enzyme was located in the acrosomal region and midpiece of these cells |
| GO:0001716 L-amino-acid oxidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: This IEA annotation from combined automated methods is correct and supported by multiple experimental IDA annotations from PMID:17356132, PMID:25767141, PMID:26673964, PMID:32818467, and PMID:32866000. Reason: Correct electronic annotation for the core molecular function, supported by extensive experimental evidence. Supporting Evidence: PMID:17356132 We showed that IL4I1 has l-amino acid oxidase activity |
| GO:0002250 adaptive immune response | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: IL4I1 plays a role in adaptive immunity by suppressing T cell activation and proliferation and promoting Treg differentiation [PMID:17356132, PMID:25778793, PMID:28891065, PMID:32818467]. However, this term is very broad and could be more specifically annotated. Reason: While IL4I1 clearly participates in adaptive immune responses through its immunomodulatory functions, this is a very broad term. More specific terms like "negative regulation of T cell proliferation" (GO:0042130) and "positive regulation of regulatory T cell differentiation" (GO:0045591) better capture IL4I1's specific roles. This broad term may be retained as non-core but is not particularly informative. Supporting Evidence: PMID:17356132 hIL4I1 inhibited the proliferation of CD3-stimulated T lymphocytes |
| GO:0002376 immune system process | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: This is a very high-level term that is correct but uninformative. IL4I1 does participate in immune system processes through its immunomodulatory effects. Reason: This term is too general to be useful. More specific immune-related annotations are present (negative regulation of T cell activation, negative regulation of T cell proliferation, positive regulation of Treg differentiation) that better describe IL4I1's actual immunological functions. Supporting Evidence: PMID:17356132 Altogether these data suggest IL4I1 as a new immunomodulatory enzyme produced by DCs. |
| GO:0002841 negative regulation of T cell mediated immune response to tumor cell | IEA GO_REF:0000117 | ACCEPT | Summary: IL4I1 has been experimentally demonstrated to suppress anti-tumor immunity and promote tumor progression through T cell suppression [PMID:32818467]. This ARBA machine learning annotation is appropriate. Reason: This annotation accurately captures a key immunological function of IL4I1 in tumor biology. Experimental evidence from PMID:32818467 directly supports this term. Supporting Evidence: PMID:32818467 It associates with reduced survival in glioma patients, promotes cancer cell motility, and suppresses adaptive immunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL) in mice |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: IL4I1 is a secreted protein, confirmed by experimental evidence showing secretion into culture medium [PMID:17356132] and secretion at the immunological synapse [PMID:28891065]. Reason: Correct electronic annotation supported by multiple IDA annotations. IL4I1 contains a signal peptide and is secreted extracellularly. Supporting Evidence: PMID:17356132 Both proteins were secreted into the culture medium |
| GO:0005737 cytoplasm | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: IL4I1 is primarily a secreted protein. While it may transit through the cytoplasm during biosynthesis, the functional localization is extracellular or in secretory compartments (lysosome). No direct experimental evidence supports cytoplasmic localization as the site of function. Reason: This ARBA annotation may reflect transient cytoplasmic presence during secretory pathway transit rather than functional localization. IL4I1 is a secreted protein with a signal peptide. The more relevant localizations are extracellular region, lysosome, and acrosomal vesicle. Supporting Evidence: PMID:17356132 Both proteins were secreted into the culture medium |
| GO:0005764 lysosome | IEA GO_REF:0000044 | ACCEPT | Summary: Lysosomal localization is inferred from UniProt subcellular location annotation. This is consistent with IL4I1's optimal activity at acidic pH and reports from mouse studies. Direct experimental evidence for human IL4I1 lysosomal localization is limited. Reason: The annotation is based on UniProt inference and is consistent with the enzyme's preference for acidic pH. UniProt cites evidence by similarity from mouse IL4I1 (O09046). Supporting Evidence: PMID:17356132 IL4I1 has l-amino acid oxidase activity, optimal at physiological pH |
| GO:0009072 aromatic amino acid metabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: IL4I1 preferentially metabolizes aromatic amino acids (Phe, Tyr, Trp) as substrates [PMID:17356132, PMID:32818467]. This ARBA annotation is appropriate and captures the substrate specificity. Reason: This accurately reflects IL4I1's substrate preference for aromatic amino acids. The enzyme preferentially oxidizes phenylalanine, tyrosine, and tryptophan to their respective alpha-keto acids. Supporting Evidence: PMID:17356132 We showed that IL4I1 has l-amino acid oxidase activity, optimal at physiological pH and primarily directed toward phenylalanine PMID:32818467 IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IL4I1 is an oxidoreductase (L-amino-acid oxidase, EC 1.4.3.2). This term is correct but very general. Reason: Correct parent term for L-amino-acid oxidase activity. While not as informative as the more specific GO:0001716, it is not wrong and provides broader context. Supporting Evidence: PMID:17356132 We showed that IL4I1 has l-amino acid oxidase activity |
| GO:0031410 cytoplasmic vesicle | IEA GO_REF:0000043 | ACCEPT | Summary: This term is a parent of acrosomal vesicle. UniProt notes IL4I1 localization to cytoplasmic secretory vesicles including acrosomes. This is consistent with IL4I1's secretory nature. Reason: IL4I1 is present in cytoplasmic vesicles including acrosomal vesicles in sperm. This broader term appropriately captures vesicular localization. Supporting Evidence: PMID:25767141 the enzyme was located in the acrosomal region and midpiece of these cells |
| GO:0045591 positive regulation of regulatory T cell differentiation | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA annotation supported by experimental evidence from PMID:25778793 demonstrating that IL4I1 promotes FoxP3+ Treg differentiation. Reason: Correct annotation with direct experimental support from IDA evidence (PMID:25778793). IL4I1 promotes Treg differentiation through phenylalanine depletion and mTORC1 signaling inhibition. Supporting Evidence: PMID:25778793 We show that IL4I1 stimulates the generation of Foxp3(+) regulatory T (Treg) cells in vitro from human and mouse T cells |
| GO:0106329 L-phenylalaine oxidase activity | IEA GO_REF:0000116 | ACCEPT | Summary: IL4I1 has been characterized as a phenylalanine oxidase with primary activity toward L-phenylalanine [PMID:17356132, PMID:25778793, PMID:26673964]. This Rhea-based annotation accurately reflects the enzyme's preferred substrate. Reason: This specific molecular function term accurately captures IL4I1's strongest substrate preference. Phenylalanine is the most efficiently oxidized substrate. Supporting Evidence: PMID:17356132 We showed that IL4I1 has l-amino acid oxidase activity, optimal at physiological pH and primarily directed toward phenylalanine PMID:25778793 IL4I1 (interleukin-4-induced gene 1) is a phenylalanine oxidase produced mainly by APCs of myeloid origin |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: This annotation comes from a large-scale neurodegenerative disease interactome mapping study that used yeast two-hybrid screening. IL4I1 was found to interact with OPTN (optineurin) and WFS1 (wolframin) based on IntAct data. However, 'protein binding' is an uninformative term that does not describe functional interactions. Reason: The term 'protein binding' (GO:0005515) is too vague to be useful for functional annotation. GO guidelines discourage this term as it provides no information about the nature of the binding or its biological relevance. The PMID:32814053 study was a high-throughput screen for neurodegenerative disease networks and IL4I1 is not primarily associated with neurodegeneration. The reported interactions (with OPTN and WFS1) lack functional validation in the context of IL4I1's known biology as an immunomodulatory enzyme. Supporting Evidence: PMID:32814053 Interactome maps are valuable resources to elucidate protein function and disease mechanisms |
| GO:0001669 acrosomal vesicle | IDA GO_REF:0000052 | ACCEPT | Summary: This annotation based on immunofluorescence curation aligns with experimental data showing IL4I1 localization to the acrosomal region of human spermatozoa. Reason: Immunofluorescence data supports acrosomal localization. Direct experimental evidence from PMID:25767141 confirms this localization. Supporting Evidence: PMID:25767141 the enzyme was located in the acrosomal region and midpiece of these cells |
| GO:0001716 L-amino-acid oxidase activity | IDA PMID:32866000 Endogenous Indole Pyruvate Pathway for Tryptophan Metabolism... | ACCEPT | Summary: This study demonstrated IL4I1 can catalyze tryptophan metabolism to produce indole derivatives (IAA, IAld), confirming L-amino acid oxidase activity toward tryptophan. Reason: Direct experimental evidence showing IL4I1 oxidizes tryptophan via the indole pyruvate pathway. Supporting Evidence: PMID:32866000 we constructed an IL4I1-overexpressed 293T cell line and found that IL4I1 can catalyze Trp to produce indole-3-acetic acid (IAA) and indole-3-carboxaldehyde (IAld) |
| GO:0001669 acrosomal vesicle | IDA PMID:25767141 Human spermatozoa possess an IL4I1 l-amino acid oxidase with... | ACCEPT | Summary: Houston et al. demonstrated IL4I1 localization to the acrosomal region of human spermatozoa by immunolocalization studies. Reason: Direct experimental evidence from immunolocalization studies in human sperm. Supporting Evidence: PMID:25767141 the enzyme was located in the acrosomal region and midpiece of these cells |
| GO:0001716 L-amino-acid oxidase activity | IDA PMID:17356132 Human IL4I1 is a secreted L-phenylalanine oxidase expressed ... | ACCEPT | Summary: Boulland et al. established that IL4I1 has L-amino acid oxidase activity, primarily toward phenylalanine, with production of H2O2 and ammonia. This is the seminal paper establishing IL4I1's enzymatic function. Reason: Core experimental evidence establishing IL4I1 as an L-amino acid oxidase. This paper demonstrated activity in stable cell lines expressing human IL4I1. Supporting Evidence: PMID:17356132 We showed that IL4I1 has l-amino acid oxidase activity, optimal at physiological pH and primarily directed toward phenylalanine |
| GO:0001716 L-amino-acid oxidase activity | IDA PMID:25767141 Human spermatozoa possess an IL4I1 l-amino acid oxidase with... | ACCEPT | Summary: Houston et al. demonstrated IL4I1 L-amino acid oxidase activity in human spermatozoa with preferred substrates phenylalanine and tryptophan. Reason: Independent experimental confirmation of LAAO activity in human sperm, extending the known expression and function context. Supporting Evidence: PMID:25767141 we demonstrate for the first time that human spermatozoa possess interleukin-induced gene 1 (IL4I1), an l-amino acid oxidase (LAAO) which is capable of generating ROS on exposure to aromatic amino acids |
| GO:0001716 L-amino-acid oxidase activity | IDA PMID:26673964 Alterations of the immunosuppressive IL4I1 enzyme activity i... | ACCEPT | Summary: Molinier-Frenkel et al. confirmed IL4I1 LAAO activity and demonstrated additional weak activity against L-arginine, as well as the effects of natural SNPs on enzyme activity. Reason: Experimental evidence confirming and extending knowledge of IL4I1 enzymatic activity, including substrate specificity toward arginine. Supporting Evidence: PMID:26673964 we show that IL4I1 activity is not only directed against phenylalanine, as initially described, but also at a lower level against arginine |
| GO:0001716 L-amino-acid oxidase activity | IDA PMID:32818467 IL4I1 Is a Metabolic Immune Checkpoint that Activates the AH... | ACCEPT | Summary: Sadik et al. demonstrated IL4I1 generates indole metabolites and kynurenic acid through L-amino acid oxidase activity on tryptophan, linking this activity to AHR activation. Reason: Key experimental evidence connecting IL4I1 LAAO activity to downstream metabolite production and AHR signaling pathway activation. Supporting Evidence: PMID:32818467 IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid |
| GO:0001772 immunological synapse | IDA PMID:28891065 IL4-induced gene 1 is secreted at the immune synapse and mod... | ACCEPT | Summary: Aubatin et al. demonstrated focal secretion of IL4I1 into the immune synaptic cleft between APCs and T cells. Reason: Direct experimental evidence from imaging studies showing IL4I1 localization at the immunological synapse, where it modulates T cell activation. Supporting Evidence: PMID:28891065 Focal secretion of IL4I1 into the immune synaptic cleft and its binding to CD3+ lymphocytes could be important in IL4I1 immunosuppressive mechanism of action |
| GO:0002819 regulation of adaptive immune response | IDA PMID:17356132 Human IL4I1 is a secreted L-phenylalanine oxidase expressed ... | MODIFY | Summary: Boulland et al. showed IL4I1 inhibits T cell proliferation, demonstrating its role in regulating adaptive immunity. Reason: While IL4I1 does regulate adaptive immunity, this term is broad. The experimental evidence more specifically supports "negative regulation" annotations such as GO:0050868 (negative regulation of T cell activation) or GO:0042130 (negative regulation of T cell proliferation) which are also annotated. The evidence shows inhibition rather than general regulation. Proposed replacements: negative regulation of adaptive immune response Supporting Evidence: PMID:17356132 hIL4I1 inhibited the proliferation of CD3-stimulated T lymphocytes with a similar effect on CD4(+) and CD8(+) T cells |
| GO:0002841 negative regulation of T cell mediated immune response to tumor cell | IDA PMID:32818467 IL4I1 Is a Metabolic Immune Checkpoint that Activates the AH... | ACCEPT | Summary: Sadik et al. demonstrated IL4I1 suppresses adaptive anti-tumor immunity and promotes tumor progression in experimental models. Reason: Direct experimental evidence showing IL4I1 suppresses T cell-mediated anti-tumor immunity, promoting tumor escape. Supporting Evidence: PMID:32818467 promotes cancer cell motility, and suppresses adaptive immunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL) in mice |
| GO:0005576 extracellular region | IDA PMID:17356132 Human IL4I1 is a secreted L-phenylalanine oxidase expressed ... | ACCEPT | Summary: Boulland et al. demonstrated IL4I1 is secreted into the culture medium, confirming extracellular localization. Reason: Direct experimental evidence showing secretion of IL4I1 protein from cells. Supporting Evidence: PMID:17356132 Both proteins were secreted into the culture medium, and we observed the secretion of endogenous human IL4I1 (hIL4I1) protein in a mediastinal lymphoma B-cell line |
| GO:0005576 extracellular region | IDA PMID:32818467 IL4I1 Is a Metabolic Immune Checkpoint that Activates the AH... | ACCEPT | Summary: Sadik et al. confirmed IL4I1 secretion and extracellular function in the tumor microenvironment. Reason: Additional experimental support for IL4I1 secretion and extracellular activity, consistent with other studies. Supporting Evidence: PMID:32818467 IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR |
| GO:0006559 L-phenylalanine catabolic process | IDA PMID:17356132 Human IL4I1 is a secreted L-phenylalanine oxidase expressed ... | ACCEPT | Summary: IL4I1 catalyzes oxidation of L-phenylalanine to phenylpyruvic acid, representing phenylalanine catabolism. Reason: Direct experimental evidence demonstrating phenylalanine as the primary substrate for IL4I1 enzymatic activity. Supporting Evidence: PMID:17356132 We showed that IL4I1 has l-amino acid oxidase activity, optimal at physiological pH and primarily directed toward phenylalanine PMID:25778793 converts phenylalanine (Phe) to phenylpyruvate, hydrogen peroxide, and ammonia |
| GO:0006559 L-phenylalanine catabolic process | IDA PMID:25767141 Human spermatozoa possess an IL4I1 l-amino acid oxidase with... | ACCEPT | Summary: Houston et al. demonstrated phenylalanine as a preferred substrate for IL4I1 LAAO activity in human spermatozoa. Reason: Independent confirmation of phenylalanine catabolism in a different cellular context (sperm). Supporting Evidence: PMID:25767141 The preferred substrates were found to be phenylalanine and tryptophan |
| GO:0006569 L-tryptophan catabolic process | IDA PMID:17356132 Human IL4I1 is a secreted L-phenylalanine oxidase expressed ... | ACCEPT | Summary: IL4I1 oxidizes tryptophan to indole-3-pyruvic acid as part of its LAAO activity. Reason: Experimental evidence supports tryptophan as a substrate, though with lower preference than phenylalanine. Supporting Evidence: PMID:17356132 We showed that IL4I1 has l-amino acid oxidase activity |
| GO:0006569 L-tryptophan catabolic process | IDA PMID:25767141 Human spermatozoa possess an IL4I1 l-amino acid oxidase with... | ACCEPT | Summary: Houston et al. confirmed tryptophan as a substrate for IL4I1 in sperm. Reason: Direct experimental evidence for tryptophan oxidation by IL4I1. Supporting Evidence: PMID:25767141 The preferred substrates were found to be phenylalanine and tryptophan |
| GO:0006572 L-tyrosine catabolic process | IDA PMID:17356132 Human IL4I1 is a secreted L-phenylalanine oxidase expressed ... | ACCEPT | Summary: IL4I1 oxidizes tyrosine to 4-hydroxyphenylpyruvic acid as part of its broad aromatic amino acid oxidase activity. Reason: Experimental evidence supports tyrosine catabolism by IL4I1, consistent with its activity on aromatic amino acids. Supporting Evidence: PMID:32818467 IL4I1 activates the AHR through the generation of indole metabolites |
| GO:0019440 obsolete L-tryptophan catabolic process to indole-3-acetate | IDA PMID:32818467 IL4I1 Is a Metabolic Immune Checkpoint that Activates the AH... | ACCEPT | Summary: Sadik et al. demonstrated IL4I1 converts tryptophan to indole-3-pyruvic acid, which leads to indole-3-acetic acid (IAA) and other indole metabolites. Reason: Key finding establishing IL4I1's role in the indole pyruvate pathway for tryptophan metabolism, distinct from the kynurenine pathway. Supporting Evidence: PMID:32818467 IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid |
| GO:0019440 obsolete L-tryptophan catabolic process to indole-3-acetate | IDA PMID:32866000 Endogenous Indole Pyruvate Pathway for Tryptophan Metabolism... | ACCEPT | Summary: Zhang et al. directly demonstrated IL4I1 produces indole-3-acetic acid (IAA) from tryptophan via the indole pyruvate pathway. Reason: Direct experimental evidence showing IL4I1-mediated production of IAA from tryptophan in an overexpression cell model. Supporting Evidence: PMID:32866000 we constructed an IL4I1-overexpressed 293T cell line and found that IL4I1 can catalyze Trp to produce indole-3-acetic acid (IAA) and indole-3-carboxaldehyde (IAld) |
| GO:0042130 negative regulation of T cell proliferation | IMP PMID:17356132 Human IL4I1 is a secreted L-phenylalanine oxidase expressed ... | ACCEPT | Summary: Boulland et al. demonstrated IL4I1 inhibits T cell proliferation through enzymatic activity-dependent H2O2 production. Mutagenesis of the catalytic glutamate (E481A) abolished activity. Reason: Key experimental finding establishing IL4I1's immunosuppressive function. The effect was shown to be dependent on enzymatic activity and H2O2 production. Supporting Evidence: PMID:17356132 hIL4I1 inhibited the proliferation of CD3-stimulated T lymphocytes with a similar effect on CD4(+) and CD8(+) T cells... hIL4I1 inhibitory effect was dependent on enzymatic activity and H(2)O(2) production |
| GO:0045577 regulation of B cell differentiation | ISS GO_REF:0000024 | UNDECIDED | Summary: This annotation is inferred from sequence similarity to mouse IL4I1. While IL4I1 was originally identified as a B cell IL4-inducible gene, direct experimental evidence for human IL4I1 regulating B cell differentiation is limited. Reason: The annotation is based on similarity to mouse ortholog. While IL4I1 is expressed in B cells and B cell lymphomas, direct evidence for regulation of B cell differentiation in humans is not available from the primary literature reviewed. UniProt notes IL4I1 "regulates the development and function of B-cells" based on mouse studies, but human-specific validation would strengthen this annotation. Supporting Evidence: PMID:17356132 Interleukin-4-induced gene 1 (IL4I1) was first described as a B-cell IL4-inducible gene |
| GO:0045591 positive regulation of regulatory T cell differentiation | IDA PMID:25778793 The immunosuppressive enzyme IL4I1 promotes FoxP3(+) regulat... | ACCEPT | Summary: Cousin et al. demonstrated IL4I1 promotes FoxP3+ Treg differentiation through phenylalanine depletion and mTORC1 signaling inhibition. Reason: Direct experimental evidence showing IL4I1 stimulates Treg generation in vitro from both human and mouse T cells. Supporting Evidence: PMID:25778793 We show that IL4I1 stimulates the generation of Foxp3(+) regulatory T (Treg) cells in vitro from human and mouse T cells |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:32818467 IL4I1 Is a Metabolic Immune Checkpoint that Activates the AH... | MODIFY | Summary: Sadik et al. showed IL4I1 activates AHR, a transcription factor. IL4I1-derived metabolites (I3P, I3A, kynurenic acid) act as AHR ligands to promote transcription. Reason: While IL4I1 metabolites do activate AHR-mediated transcription, this is an indirect effect through metabolite production rather than direct transcriptional regulation by IL4I1 protein itself. A more accurate annotation would reflect AHR pathway activation. The term GO:0045944 is very broad and does not capture the specific mechanism. Proposed replacements: negative regulation of cellular response to stimulus gene expression Supporting Evidence: PMID:32818467 IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid PMID:32866000 both IAA and IAld are accumulated in dendritic cells (DCs) and can stimulate the expression of CYP1A1 |
| GO:0050868 negative regulation of T cell activation | IDA PMID:28891065 IL4-induced gene 1 is secreted at the immune synapse and mod... | ACCEPT | Summary: Aubatin et al. demonstrated IL4I1 decreases early signaling events downstream of TCR stimulation, resulting in T cell inhibition. Reason: Direct experimental evidence showing IL4I1 suppresses T cell activation through effects on TCR signaling. Supporting Evidence: PMID:28891065 the presence of IL4I1 during T-cell activation decreases early signaling events downstream of TCR stimulation, resulting in global T-cell inhibition |
| GO:0097225 sperm midpiece | IDA PMID:25767141 Human spermatozoa possess an IL4I1 l-amino acid oxidase with... | ACCEPT | Summary: Houston et al. localized IL4I1 to the midpiece of human spermatozoa in addition to the acrosomal region. Reason: Direct experimental evidence from immunolocalization studies showing IL4I1 presence in the sperm midpiece. Supporting Evidence: PMID:25767141 the enzyme was located in the acrosomal region and midpiece of these cells |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2160492 | ACCEPT | Summary: Reactome pathway annotation for "IL4I1:FAD oxidises L-Phe to kPPV" indicates extracellular localization for the reaction. This is consistent with IL4I1 being a secreted enzyme. Reason: Consistent with multiple experimental studies showing IL4I1 secretion. Reactome annotation reflects established knowledge of IL4I1 localization. Supporting Evidence: PMID:17356132 Both proteins were secreted into the culture medium |
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Download this section (compressed HTML)Q: What is the relative contribution of enzymatic activity versus non-enzymatic mechanisms to IL4I1's immunosuppressive effects? PMID:28891065 suggests some T cell inhibition occurs independently of enzymatic activity, but PMID:32818467 emphasizes the importance of Trp metabolism and AHR activation.
Q: Does IL4I1 have a physiological role in sperm function beyond capacitation? IL4I1 localizes to acrosome and midpiece but functional significance in fertilization is not fully established.
Experiment: Test whether IL4I1 knockout or inhibition affects anti-tumor T cell responses in human tumor microenvironment models to validate the metabolic checkpoint function.
Experiment: Determine whether IL4I1 localizes to and functions at the immunological synapse in vivo, and whether AHR activation occurs locally at the synapse.
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