IL4I1

Existing Annotations Review

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

Core Functions

IL4I1 is an FAD-dependent L-amino acid oxidase (EC 1.4.3.2, EC 1.4.3.25) that catalyzes the oxidative deamination of L-amino acids to alpha-keto acids with production of hydrogen peroxide and ammonia. Primary substrates are aromatic amino acids: phenylalanine (highest activity), tyrosine, and tryptophan. Weak activity against L-arginine has also been demonstrated. This enzymatic activity underlies all of IL4I1's biological functions.

Molecular Function:

L-amino-acid oxidase 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:25767141
The preferred substrates were found to be phenylalanine and tryptophan
PMID:26673964
we show that IL4I1 activity is not only directed against phenylalanine, as initially described, but also at a lower level against arginine

IL4I1 mediates an endogenous indole pyruvate pathway for tryptophan metabolism, converting Trp to indole-3-pyruvic acid (I3P), which gives rise to indole-3-acetic acid (IAA), indole-3-aldehyde (I3A), and kynurenic acid. These metabolites are potent aryl hydrocarbon receptor (AHR) agonists, linking IL4I1 enzymatic activity to immunomodulation and tumor biology.

Molecular Function:

L-amino-acid oxidase activity

Directly Involved In:

L-tryptophan catabolic process

Supporting Evidence:

PMID:32818467
IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid
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)

IL4I1 inhibits T cell proliferation through H2O2 production (dependent on enzymatic activity) and phenylalanine depletion affecting mTORC1 signaling. This immunosuppressive function is central to IL4I1's role in adaptive immunity and tumor immune evasion.

Molecular Function:

L-amino-acid oxidase activity

Directly Involved In:

negative regulation of T cell proliferation

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
PMID:25778793
IL4I1 inhibits T-cell proliferation via hydrogen peroxide toxicity on effector/memory T cells

IL4I1 promotes FoxP3+ regulatory T cell differentiation through phenylalanine consumption and mTORC1 signaling inhibition. This contributes to the overall immunosuppressive phenotype induced by IL4I1 expression.

Molecular Function:

L-amino-acid oxidase activity

Directly Involved In:

positive regulation of regulatory T cell differentiation

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

References

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000116

Automatic Gene Ontology annotation based on Rhea mapping

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:17356132

Human IL4I1 is a secreted L-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation.

IL4I1 has L-amino acid oxidase activity, primarily toward phenylalanine

"We showed that IL4I1 has l-amino acid oxidase activity, optimal at physiological pH and primarily directed toward phenylalanine."
IL4I1 is secreted into extracellular medium

"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, MedB-1."
IL4I1 inhibits T cell proliferation via H2O2 production

"hIL4I1 inhibited the proliferation of CD3-stimulated T lymphocytes with a similar effect on CD4(+) and CD8(+) T cells. In contrast, memory T cells were more strongly affected by hIL4I1 and its catabolite H(2)O(2) than naive T cells. hIL4I1 inhibitory effect was dependent on enzymatic activity and H(2)O(2) production"
Expressed by mature dendritic cells and macrophages

"Immunohistochemical analysis of secondary lymphoid organs showed staining of germinal center macrophages and inflammatory myeloid cells. In vitro, functional enzyme was highest in mature dendritic cells (DCs), suggesting a role in antigen-presenting cell/T-lymphocyte cross-talk."

PMID:25767141

Human spermatozoa possess an IL4I1 l-amino acid oxidase with a potential role in sperm function.

IL4I1 is present in human spermatozoa

"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 in the presence of oxygen."
Localized to acrosomal region and midpiece

"the enzyme was located in the acrosomal region and midpiece of these cells."
Preferred substrates are phenylalanine and tryptophan

"The preferred substrates were found to be phenylalanine and tryptophan"
May regulate capacitation and acrosomal exocytosis

"Stimulation of LAAO activity resulted in the induction of several hallmarks of capacitation including tyrosine phosphorylation of the sperm flagellum and concomitant activation of phospho-SRC expression. In addition, stimulation of LAAO resulted in an increase in the levels of acrosomal exocytosis in both the presence and absence of progesterone stimulation"

PMID:25778793

The immunosuppressive enzyme IL4I1 promotes FoxP3(+) regulatory T lymphocyte differentiation.

IL4I1 promotes FoxP3+ Treg differentiation

"We show that IL4I1 stimulates the generation of Foxp3(+) regulatory T (Treg) cells in vitro from human and mouse T cells."
Effect mediated through phenylalanine consumption and mTORC1 inhibition

"Analysis of Treg-cell induction under conditions of Phe deprivation and hydrogen peroxide addition suggests that Phe consumption by the enzyme participates in Treg-cell enrichment. In line with this hypothesis, IL4I1 inhibits mTORC1 signaling shortly after T-cell activation."
IL4I1 limits Th1 and Th2 polarization

"Conversely, IL4I1 limits Th1 and Th2 polarization while modifying the Th17 phenotype, in particular, by inducing its own production."

PMID:26673964

Alterations of the immunosuppressive IL4I1 enzyme activity induced by naturally occurring SNP/mutations.

IL4I1 also has weak activity against L-arginine

"we show that IL4I1 activity is not only directed against phenylalanine, as initially described, but also at a lower level against arginine."
Natural SNPs can alter enzyme activity (N92D hyperactive, R102G hypomorphic)

"The N92D SNP leads to a hyperactive enzyme, while the R102G mutation is hypomorphic."

PMID:28891065

IL4-induced gene 1 is secreted at the immune synapse and modulates TCR activation independently of its enzymatic activity.

IL4I1 is secreted at the immunological synapse

"Focal secretion of IL4I1 into the immune synaptic cleft and its binding to CD3+ lymphocytes could be important in IL4I1 immunosuppressive mechanism of action."
Decreases TCR signaling events

"the presence of IL4I1 during T-cell activation decreases early signaling events downstream of TCR stimulation, resulting in global T-cell inhibition which is more pronounced when there is CD28 costimulation."
Some effects independent of enzymatic activity

"Surprisingly, the enzymatic activity of IL4I1 is not involved."

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

High-throughput Y2H interactome screen

"Here, we report on an interactome map that focuses on neurodegenerative disease (ND), connects ∼5,000 human proteins via ∼30,000 candidate interactions and is generated by systematic yeast two-hybrid interaction screening of ∼500 ND-related proteins and integration of literature interactions."
IL4I1 identified in network but not primary focus of study

"Interactome maps are valuable resources to elucidate protein function and disease mechanisms."

PMID:32818467

IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression.

IL4I1 activates AHR through indole metabolites and kynurenic acid

"IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid."
Suppresses anti-tumor immunity

"suppresses adaptive immunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL) in mice."
Promotes tumor progression

"promotes cancer cell motility, and suppresses adaptive immunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL) in mice."
Associates with poor prognosis in glioma

"It associates with reduced survival in glioma patients"

PMID:32866000

Endogenous Indole Pyruvate Pathway for Tryptophan Metabolism Mediated by IL4I1.

IL4I1 catalyzes Trp to IAA and IAld production

"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)."
Establishes endogenous indole pyruvate pathway in host cells

"Our results demonstrate the existence of the indole pyruvate pathway in host cells with IL4I1 as the key enzyme."
Products activate AHR through CYP1A1 expression

"both IAA and IAld are accumulated in dendritic cells (DCs) and can stimulate the expression of CYP1A1."

Reactome:R-HSA-2160492

IL4I1:FAD oxidises L-Phe to kPPV

Reactome pathway annotation for phenylalanine metabolism

"Extracellular L-amino-acid oxidase (IL4I1) catalyzes the reaction of phenylalanine, water, and molecular oxygen to form keto-phenylpyruvate, ammonia, and hydrogen peroxide. IL4I1, inferred to form a complex with FAD, has L-amino acid oxidase activity and with a strong preference for phenylalanine."

file:human/IL4I1/IL4I1-deep-research-falcon.md

Deep research on IL4I1 function

Suggested Experiments

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.

Deep Research

Falcon

(IL4I1-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 28 citations 2025-12-23T13:46:47.132368

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Plan and verification
- Target verification: The gene symbol IL4I1 refers to human interleukin-4-induced gene 1 (UniProt Q96RQ9), a secreted L-amino-acid oxidase in the flavin monoamine oxidase family. 2023–2024 sources consistently describe human IL4I1 as a secreted LAAO that acts on aromatic L-amino acids and is expressed by antigen-presenting cells and tumor-associated macrophages, matching the UniProt description (organism: Homo sapiens; domains consistent with FAD-dependent amine oxidases). No symbol ambiguity was detected in the surveyed literature (grobben2024targetingaminoacidmetabolizing pages 16-18, seo2023immuneregulationthrough pages 4-5, shen2024il4inducedgene1 pages 1-2).

Key concepts and definitions
- Molecular identity and reaction: IL4I1 encodes a secreted L-amino acid oxidase (EC 1.4.3.2/1.4.3.25) that oxidizes L-amino acids to their corresponding alpha-keto acids with concomitant generation of hydrogen peroxide (H2O2) and ammonia (NH3). It preferentially targets aromatic amino acids—L-phenylalanine (Phe), L-tyrosine (Tyr), and L-tryptophan (Trp)—with Phe/Tyr generally favored over Trp; Trp is oxidized to indole-3-pyruvic acid (I3P) (Grobben 2024, Frontiers in Immunology, Aug 2024, doi:10.3389/fimmu.2024.1440269; Seo & Kwon 2023, Experimental & Molecular Medicine, Jul 2023, doi:10.1038/s12276-023-01028-7) (grobben2024targetingaminoacidmetabolizing pages 16-18, seo2023immuneregulationthrough pages 4-5, grobben2024targetingaminoacidmetabolizing pages 18-19).
- AHR-linked immunometabolism: IL4I1’s Trp metabolism provides an endogenous indole–pyruvate pathway that yields I3P and downstream indole derivatives (indole-3-aldehyde, indole-3-acetic acid, indole-3-lactic acid) and kynurenic acid (KynA), which are aryl hydrocarbon receptor (AHR) agonists. These metabolites activate AHR signaling and contribute to immunosuppression in the tumor microenvironment (TME) (Seo & Kwon 2023; Grobben 2024) (seo2023immuneregulationthrough pages 4-5, grobben2024targetingaminoacidmetabolizing pages 18-19, zhang2024newinsightinto pages 7-8).
- Cellular sources and location of action: IL4I1 is induced in antigen-presenting cells (APCs)—notably dendritic cells, macrophages, and B cells—and is often enriched in tumor-associated macrophages (TAMs) in solid tumors. IL4I1 contains a signal peptide and is secreted; it can also localize to lysosomes and has activity favored by acidic pH. Its immunomodulatory effects are largely mediated extracellularly/pericellularly via H2O2 and diffusible metabolites at immune interfaces (Shen et al. 2024, Reviews in Cardiovascular Medicine, Sep 2024, doi:10.31083/j.rcm2509337; Ye et al. 2024, Frontiers in Immunology, Jan 2024, doi:10.3389/fimmu.2023.1338244) (shen2024il4inducedgene1 pages 1-2, ye2024il4i1inm2like pages 15-16, ye2024il4i1inm2like pages 1-2, ye2024il4i1inm2like pages 16-18).

Recent developments and latest research (2023–2024)
- Enzymology and AHR activation: 2023–2024 reviews consolidate that IL4I1 converts Phe→phenylpyruvate, Tyr→4-hydroxyphenylpyruvate, Trp→indole-3-pyruvate, producing H2O2 and NH3. IL4I1-derived indole metabolites (I3P, I3A, KynA) are potent AHR agonists; pan-cancer analyses suggest stronger association of IL4I1 expression with AHR activation than IDO/TDO in some datasets (Grobben 2024; Griffith & Frankel 2024, Cancers, Jan 2024, doi:10.3390/cancers16030472) (grobben2024targetingaminoacidmetabolizing pages 18-19, griffith2024thearylhydrocarbon pages 10-12).
- Tumor microenvironment roles: Single-cell and functional analyses in glioma show IL4I1 is predominantly expressed in M2-like TAMs and promotes glioma invasion/migration, correlating with immune checkpoint expression and worse prognosis (Ye et al. 2024) (ye2024il4i1inm2like pages 15-16, ye2024il4i1inm2like pages 16-18, ye2024il4i1inm2like pages 9-11). Pan-cancer work links high IL4I1 to increased TAM infiltration and immune checkpoint gene expression (Chen et al. 2024, Discover Oncology, May 2024, doi:10.1007/s12672-024-01000-5) (chen2024pancanceranalysisof pages 5-10).
- Immune regulation through Trp metabolism: 2023 synthesis emphasizes that Trp metabolites—including IL4I1-derived I3P/I3A and KynA—converge on AHR to modulate immune responses and tissue homeostasis, with implications for cancer and inflammatory disease (Seo & Kwon 2023) (seo2023immuneregulationthrough pages 4-5).

Catalytic function and substrate specificity
- Reaction: L-amino acid + O2 + H2O → alpha-keto acid + NH3 + H2O2. Preferred substrates are aromatic amino acids: Phe and Tyr (higher efficiency), Trp (lower affinity). Products include phenylpyruvic acid (from Phe), 4-hydroxyphenylpyruvic acid (from Tyr), and indole-3-pyruvic acid (from Trp); H2O2 and NH3 are co-products (Grobben 2024; Seo & Kwon 2023) (grobben2024targetingaminoacidmetabolizing pages 16-18, seo2023immuneregulationthrough pages 4-5, grobben2024targetingaminoacidmetabolizing pages 18-19).
- AHR-activating metabolites: I3P can convert to I3A, IAA, ILA, and KynA; I3P and I3A notably act as potent AHR agonists, linking IL4I1 activity to AHR signaling (Seo & Kwon 2023; Grobben 2024) (seo2023immuneregulationthrough pages 4-5, grobben2024targetingaminoacidmetabolizing pages 18-19, zhang2024newinsightinto pages 7-8).

Localization and where IL4I1 acts
- Expression: Highest in immune organs and in APCs; in cancers, enriched in TAMs and sometimes stromal cells. IL4I1 is secreted and also reported in lysosomal compartments; functional activity is prominent in the extracellular TME, influencing T cells and macrophage polarization via H2O2 and indole metabolites (Shen 2024; Ye 2024) (shen2024il4inducedgene1 pages 1-2, ye2024il4i1inm2like pages 15-16, ye2024il4i1inm2like pages 16-18).
- Site of action: At immune interfaces in the TME, IL4I1-generated H2O2 can inhibit TCR signaling and proliferation; indole metabolites activate AHR in immune/tumor cells, collectively promoting Treg differentiation, suppressing effector T cells, and favoring M2 polarization (Grobben 2024; Chen 2024) (grobben2024targetingaminoacidmetabolizing pages 16-18, chen2024pancanceranalysisof pages 5-10).

Current applications and real-world implementations
- Biomarker and prognostic associations (pan-cancer): IL4I1 mRNA/protein overexpression is observed across many tumors; IL4I1 levels and methylation associate with pathological stage and survival, variably by tumor type (Chen 2024, Discover Oncology, May 2024, doi:10.1007/s12672-024-01000-5) (chen2024pancanceranalysisof pages 5-10, chen2024pancanceranalysisof pages 14-18).
- Immunotherapy response: In bladder cancer (IMvigor210 anti–PD-L1 cohort), higher IL4I1 expression marked an inflamed TME, basal subtype, and was associated with higher immunotherapy response rates and improved survival (Peng et al. 2024, Frontiers in Pharmacology, May 2024, doi:10.3389/fphar.2024.1365683) (peng2024il4i1anovel pages 12-13, peng2024il4i1anovel pages 13-15, peng2024il4i1anovel pages 1-2).
- Resistance contexts: IL4I1 is reported to be upregulated after anti–PD-1 therapy and may mediate resistance by suppressing CD8+ T-cell infiltration and inducing PD-1/TIM3 on T cells in ex vivo models (Grobben 2024) (grobben2024targetingaminoacidmetabolizing pages 18-19, grobben2024targetingaminoacidmetabolizing pages 16-18).

Translational therapies and combinations
- Direct IL4I1 inhibitors: Preclinical probes have been reported, including CB-668 (a selective oral IL4I1 inhibitor) with single-agent activity and synergy with anti–PD-L1 in mice; patent activity for IL4I1 inhibitors (WIPO filings 2021–2022) underscores translational interest (Grobben 2024) (grobben2024targetingaminoacidmetabolizing pages 18-19, grobben2024targetingaminoacidmetabolizing pages 29-29).
- Targeting downstream AHR: Given strong associations of IL4I1 with AHR activation, AHR inhibitors are under early clinical study; interim phase I results for the oral AHR inhibitor BAY2416964 noted 32.8% stable disease among 67 patients, highlighting activity of AHR blockade in humans (Griffith & Frankel 2024, Cancers, Jan 2024, doi:10.3390/cancers16030472) (griffith2024thearylhydrocarbon pages 10-12).
- Rational combinations: Reviews propose combining IL4I1 inhibition with IDO/TDO blockade or AHR inhibitors to address compensatory Trp metabolism and AHR-driven immunosuppression (Griffith & Frankel 2024; Grobben 2024) (griffith2024thearylhydrocarbon pages 10-12, grobben2024targetingaminoacidmetabolizing pages 18-19, grobben2024targetingaminoacidmetabolizing pages 16-18).

Expert opinions and analysis
- Immunometabolism consensus: 2023–2024 reviews converge on IL4I1 as a metabolic immune checkpoint, with a broader and often stronger linkage to AHR activation than IDO/TDO in some tumor contexts; this may underlie limited efficacy of IDO1 inhibition alone and supports combination strategies (Seo & Kwon 2023; Griffith & Frankel 2024; Grobben 2024) (seo2023immuneregulationthrough pages 4-5, griffith2024thearylhydrocarbon pages 10-12, grobben2024targetingaminoacidmetabolizing pages 18-19).
- Macrophage-centric view: Single-cell analyses emphasize IL4I1’s predominant expression in M2-like TAMs, positioning it as a TAM-associated target for immunotherapy and as a prognostic marker in glioma and other solid tumors (Ye 2024) (ye2024il4i1inm2like pages 15-16, ye2024il4i1inm2like pages 16-18, ye2024il4i1inm2like pages 9-11).

Relevant statistics and data
- Clinical AHR inhibitor: BAY2416964 phase I interim showed 32.8% stable disease among 67 treated patients (Griffith & Frankel 2024, summarizing clinical reports) (griffith2024thearylhydrocarbon pages 10-12).
- Pan-cancer correlations: IL4I1 expression/methylation correlates with survival metrics in multiple tumor types; drug-sensitivity analyses suggest associations with resistance to docetaxel and BMS-754807 and sensitivity to temozolomide (Chen 2024) (chen2024pancanceranalysisof pages 14-18).
- Immunotherapy cohort: In IMvigor210 (BLCA), high IL4I1 was associated with improved ICB response and survival, consistent with an inflamed TME signature (Peng 2024) (peng2024il4i1anovel pages 13-15, peng2024il4i1anovel pages 1-2).

Structured evidence summary
| Concept / claim | Specific details | Evidence type | Year | Journal | URL / DOI | Context IDs |
|---|---|---:|---:|---|---|---|
| Enzymatic reaction & preferred substrates/products | Secreted L-amino acid oxidase (LAAO) that oxidizes aromatic L-amino acids (L-Phe, L-Tyr, L-Trp) to corresponding α-keto acids (e.g., phenylpyruvic acid, 4‑hydroxyphenylpyruvic acid, indole‑3‑pyruvic acid) with concomitant H2O2 and NH3 release; Phe/Tyr preferred over Trp (Trp oxidized with lower affinity). | Review(s) summarizing biochemical and enzymology data | 2023–2024 | Frontiers in Immunology; Experimental & Molecular Medicine | https://doi.org/10.3389/fimmu.2024.1440269; https://doi.org/10.1038/s12276-023-01028-7 | (grobben2024targetingaminoacidmetabolizing pages 16-18, seo2023immuneregulationthrough pages 4-5, grobben2024targetingaminoacidmetabolizing pages 18-19, zhang2024newinsightinto pages 12-13) |
| AHR-activating metabolites from Trp (I3P, I3A, KynA) | IL4I1 produces indole-3-pyruvic acid (I3P) from Trp which can convert to indole-3-aldehyde (I3A), indole-3-acetic acid, indole-3-lactic acid and kynurenic acid (KynA); these indole/kynurenine-family metabolites are potent AHR agonists and can drive AHR signaling in the TME. | Review(s) and mechanistic summaries | 2023–2024 | Experimental & Molecular Medicine; Frontiers in Immunology | https://doi.org/10.1038/s12276-023-01028-7; https://doi.org/10.3389/fimmu.2024.1440269 | (seo2023immuneregulationthrough pages 4-5, grobben2024targetingaminoacidmetabolizing pages 18-19, zhang2024newinsightinto pages 7-8) |
| Secretion & cell-type localization | IL4I1 contains a signal peptide and is secreted; highest expression in antigen-presenting cells (dendritic cells, macrophages, B cells), tumor-associated macrophages (TAMs) and certain stromal cells; evidence for lysosomal/acidic-pH intracellular localization in addition to extracellular/pericellular secretion. | Review + primary/single-cell analyses | 2024 | Reviews in Cardiovascular Medicine; Frontiers in Immunology | https://doi.org/10.31083/j.rcm2509337; https://doi.org/10.3389/fimmu.2023.1338244 | (shen2024il4inducedgene1 pages 1-2, ye2024il4i1inm2like pages 15-16, ye2024il4i1inm2like pages 1-2, peng2024il4i1anovel pages 12-13, ye2024il4i1inm2like pages 16-18) |
| Tumor microenvironment actions & immune-synapse/extracellular activity | IL4I1 activity in the extracellular TME generates H2O2 and oncometabolites that suppress effector T cells, raise activation thresholds, promote Treg differentiation and M2 polarization, and activate AHR signaling; effects occur via extracellular/pericellular metabolism and diffusible metabolites rather than only intracellular action. | Review + pan-cancer analyses | 2023–2024 | Frontiers in Immunology; Frontiers in Immunology (reviews) | https://doi.org/10.3389/fimmu.2024.1440269; https://doi.org/10.3389/fimmu.2023.1338244 | (grobben2024targetingaminoacidmetabolizing pages 18-19, grobben2024targetingaminoacidmetabolizing pages 16-18, chen2024pancanceranalysisof pages 5-10) |
| Prognostic / biomarker associations (pan‑cancer; BLCA IMvigor210) | IL4I1 is overexpressed across many tumors; expression/methylation correlates with stage and survival variably by tumor type; in bladder cancer (IMvigor210 cohort) high IL4I1 associated with an inflamed TME, basal subtype and higher ICB response rates in some analyses. | Pan-cancer analyses + cohort validation | 2024 | Discover Oncology; Frontiers in Pharmacology | https://doi.org/10.1007/s12672-024-01000-5; https://doi.org/10.3389/fphar.2024.1365683 | (chen2024pancanceranalysisof pages 5-10, chen2024pancanceranalysisof pages 14-18, peng2024il4i1anovel pages 12-13, peng2024il4i1anovel pages 13-15, peng2024il4i1anovel pages 1-2) |
| Translational targeting & therapeutic context | Preclinical and patent activity for IL4I1 inhibitors (e.g., reported CB‑668 preclinical probe); IL4I1 upregulation observed after anti‑PD‑1 therapy and may mediate ICI resistance; proposed strategies include IL4I1 inhibitors alone or combined with IDO/TDO or AHR pathway blockade. | Review + translational reports / patent literature | 2023–2024 | Frontiers in Immunology; Cancers | https://doi.org/10.3389/fimmu.2024.1440269; https://doi.org/10.3390/cancers16030472 | (grobben2024targetingaminoacidmetabolizing pages 18-19, grobben2024targetingaminoacidmetabolizing pages 29-29, grobben2024targetingaminoacidmetabolizing pages 16-18, griffith2024thearylhydrocarbon pages 10-12) |
| Macrophage M2 polarization & glioma TAM expression | Single-cell and experimental co-culture data show IL4I1 is enriched in M2-like TAMs in glioma, where it promotes M2 polarization and enhances glioma invasion/migration; IL4I1 expression in TAMs correlates with immune checkpoints and worse prognosis in glioma. | Primary single-cell and in vitro study | 2024 | Frontiers in Immunology | https://doi.org/10.3389/fimmu.2023.1338244 | (ye2024il4i1inm2like pages 15-16, ye2024il4i1inm2like pages 1-2, ye2024il4i1inm2like pages 16-18, ye2024il4i1inm2like pages 9-11) |
| Quantitative / statistical nuggets (translational readouts) | Preclinical IL4I1 inhibition (CB‑668) showed anti‑tumor activity and synergy with anti‑PD‑L1 in mice; phase I AhR inhibitor BAY2416964 reported 32.8% stable disease in 67 patients (example of targeting downstream AHR); pan‑cancer drug‑sensitivity correlations show IL4I1 expression correlates with resistance to some agents (e.g., docetaxel) in GDSC analyses. | Preclinical reports, early clinical AhR data, pan‑cancer drug‑sensitivity analysis | 2023–2024 | Frontiers in Immunology; Cancers; Discover Oncology | https://doi.org/10.3389/fimmu.2024.1440269; https://doi.org/10.3390/cancers16030472; https://doi.org/10.1007/s12672-024-01000-5 | (grobben2024targetingaminoacidmetabolizing pages 18-19, griffith2024thearylhydrocarbon pages 10-12, chen2024pancanceranalysisof pages 14-18, peng2024il4i1anovel pages 12-13) |

Table: Concise, cited evidence table summarizing IL4I1 (Q96RQ9) enzymology, metabolites, localization, TME actions, biomarker associations, translational status and quantitative findings from 2023–2024 sources. Useful for quickly mapping claims to primary reviews and studies (pqac IDs).

Conclusion
Human IL4I1 (Q96RQ9) is a secreted, FAD-dependent L-amino-acid oxidase that preferentially oxidizes aromatic amino acids (Phe, Tyr, Trp) to alpha-keto acids with H2O2 and NH3 production. Its tryptophan metabolism feeds an indole–pyruvate branch that generates potent AHR agonists (I3P/I3A/KynA), linking IL4I1 to immunosuppressive signaling in the tumor microenvironment. 2023–2024 studies localize IL4I1 predominantly to antigen-presenting cells and TAMs, acting extracellularly/pericellularly to inhibit effector T cells, promote Treg and M2 phenotypes, and modulate checkpoint activity. Translationally, IL4I1 serves as a prognostic/immunologic biomarker across cancers, with cohort data supporting predictive value for immunotherapy in bladder cancer, and it is implicated in resistance to PD-1/PD-L1 blockade. Emerging small-molecule inhibitors (e.g., CB-668) and the clinical development of AHR inhibitors support targeting this axis, with expert analyses endorsing combinatorial strategies (IL4I1±IDO/TDO±AHR) to overcome metabolic immune evasion (grobben2024targetingaminoacidmetabolizing pages 16-18, seo2023immuneregulationthrough pages 4-5, grobben2024targetingaminoacidmetabolizing pages 18-19, shen2024il4inducedgene1 pages 1-2, ye2024il4i1inm2like pages 15-16, chen2024pancanceranalysisof pages 5-10, griffith2024thearylhydrocarbon pages 10-12, chen2024pancanceranalysisof pages 14-18, peng2024il4i1anovel pages 13-15).

References

(grobben2024targetingaminoacidmetabolizing pages 16-18): Yvonne Grobben. Targeting amino acid-metabolizing enzymes for cancer immunotherapy. Frontiers in Immunology, Aug 2024. URL: https://doi.org/10.3389/fimmu.2024.1440269, doi:10.3389/fimmu.2024.1440269. This article has 14 citations and is from a peer-reviewed journal.
(seo2023immuneregulationthrough pages 4-5): Su-Kil Seo and Byungsuk Kwon. Immune regulation through tryptophan metabolism. Experimental & Molecular Medicine, 55:1371-1379, Jul 2023. URL: https://doi.org/10.1038/s12276-023-01028-7, doi:10.1038/s12276-023-01028-7. This article has 233 citations and is from a peer-reviewed journal.
(shen2024il4inducedgene1 pages 1-2): Rui Shen, Yan Ding, Qian Dong, Yue Wang, Jian Yu, Chengliang Pan, Yifan Cai, Zhiyang Li, Jiangmei Zhang, Kunwu Yu, and Qiutang Zeng. Il-4-induced gene 1: a potential player in myocardial infarction. Reviews in Cardiovascular Medicine, Sep 2024. URL: https://doi.org/10.31083/j.rcm2509337, doi:10.31083/j.rcm2509337. This article has 1 citations and is from a peer-reviewed journal.
(grobben2024targetingaminoacidmetabolizing pages 18-19): Yvonne Grobben. Targeting amino acid-metabolizing enzymes for cancer immunotherapy. Frontiers in Immunology, Aug 2024. URL: https://doi.org/10.3389/fimmu.2024.1440269, doi:10.3389/fimmu.2024.1440269. This article has 14 citations and is from a peer-reviewed journal.
(zhang2024newinsightinto pages 7-8): Kangling Zhang, Abhishek Mishra, and Chinnaswamy Jagannath. New insight into arginine and tryptophan metabolism in macrophage activation during tuberculosis. Frontiers in Immunology, Apr 2024. URL: https://doi.org/10.3389/fimmu.2024.1363938, doi:10.3389/fimmu.2024.1363938. This article has 29 citations and is from a peer-reviewed journal.
(ye2024il4i1inm2like pages 15-16): Feng Ye, Lichong Wang, Yuanyou Li, Chengyuan Dong, Liangxue Zhou, and Jianguo Xu. Il4i1 in m2-like macrophage promotes glioma progression and is a promising target for immunotherapy. Frontiers in Immunology, Jan 2024. URL: https://doi.org/10.3389/fimmu.2023.1338244, doi:10.3389/fimmu.2023.1338244. This article has 16 citations and is from a peer-reviewed journal.
(ye2024il4i1inm2like pages 1-2): Feng Ye, Lichong Wang, Yuanyou Li, Chengyuan Dong, Liangxue Zhou, and Jianguo Xu. Il4i1 in m2-like macrophage promotes glioma progression and is a promising target for immunotherapy. Frontiers in Immunology, Jan 2024. URL: https://doi.org/10.3389/fimmu.2023.1338244, doi:10.3389/fimmu.2023.1338244. This article has 16 citations and is from a peer-reviewed journal.
(ye2024il4i1inm2like pages 16-18): Feng Ye, Lichong Wang, Yuanyou Li, Chengyuan Dong, Liangxue Zhou, and Jianguo Xu. Il4i1 in m2-like macrophage promotes glioma progression and is a promising target for immunotherapy. Frontiers in Immunology, Jan 2024. URL: https://doi.org/10.3389/fimmu.2023.1338244, doi:10.3389/fimmu.2023.1338244. This article has 16 citations and is from a peer-reviewed journal.
(griffith2024thearylhydrocarbon pages 10-12): Brian D. Griffith and Timothy L. Frankel. The aryl hydrocarbon receptor: impact on the tumor immune microenvironment and modulation as a potential therapy. Cancers, 16:472, Jan 2024. URL: https://doi.org/10.3390/cancers16030472, doi:10.3390/cancers16030472. This article has 22 citations and is from a poor quality or predatory journal.
(ye2024il4i1inm2like pages 9-11): Feng Ye, Lichong Wang, Yuanyou Li, Chengyuan Dong, Liangxue Zhou, and Jianguo Xu. Il4i1 in m2-like macrophage promotes glioma progression and is a promising target for immunotherapy. Frontiers in Immunology, Jan 2024. URL: https://doi.org/10.3389/fimmu.2023.1338244, doi:10.3389/fimmu.2023.1338244. This article has 16 citations and is from a peer-reviewed journal.
(chen2024pancanceranalysisof pages 5-10): Bin Chen, Yi Liu, Yuping He, and Chenfu Shen. Pan-cancer analysis of prognostic and immunological role of il4i1 in human tumors: a bulk omics research and single cell sequencing validation. Discover Oncology, May 2024. URL: https://doi.org/10.1007/s12672-024-01000-5, doi:10.1007/s12672-024-01000-5. This article has 3 citations and is from a poor quality or predatory journal.
(chen2024pancanceranalysisof pages 14-18): Bin Chen, Yi Liu, Yuping He, and Chenfu Shen. Pan-cancer analysis of prognostic and immunological role of il4i1 in human tumors: a bulk omics research and single cell sequencing validation. Discover Oncology, May 2024. URL: https://doi.org/10.1007/s12672-024-01000-5, doi:10.1007/s12672-024-01000-5. This article has 3 citations and is from a poor quality or predatory journal.
(peng2024il4i1anovel pages 12-13): Xiangrong Peng, Chuan Liu, Li Zhang, Yin Chen, Lixin Mao, Shenglin Gao, Xiaokai Shi, and Li Zuo. Il4i1: a novel molecular biomarker represents an inflamed tumor microenvironment and precisely predicts the molecular subtype and immunotherapy response of bladder cancer. Frontiers in Pharmacology, May 2024. URL: https://doi.org/10.3389/fphar.2024.1365683, doi:10.3389/fphar.2024.1365683. This article has 3 citations and is from a poor quality or predatory journal.
(peng2024il4i1anovel pages 13-15): Xiangrong Peng, Chuan Liu, Li Zhang, Yin Chen, Lixin Mao, Shenglin Gao, Xiaokai Shi, and Li Zuo. Il4i1: a novel molecular biomarker represents an inflamed tumor microenvironment and precisely predicts the molecular subtype and immunotherapy response of bladder cancer. Frontiers in Pharmacology, May 2024. URL: https://doi.org/10.3389/fphar.2024.1365683, doi:10.3389/fphar.2024.1365683. This article has 3 citations and is from a poor quality or predatory journal.
(peng2024il4i1anovel pages 1-2): Xiangrong Peng, Chuan Liu, Li Zhang, Yin Chen, Lixin Mao, Shenglin Gao, Xiaokai Shi, and Li Zuo. Il4i1: a novel molecular biomarker represents an inflamed tumor microenvironment and precisely predicts the molecular subtype and immunotherapy response of bladder cancer. Frontiers in Pharmacology, May 2024. URL: https://doi.org/10.3389/fphar.2024.1365683, doi:10.3389/fphar.2024.1365683. This article has 3 citations and is from a poor quality or predatory journal.
(grobben2024targetingaminoacidmetabolizing pages 29-29): Yvonne Grobben. Targeting amino acid-metabolizing enzymes for cancer immunotherapy. Frontiers in Immunology, Aug 2024. URL: https://doi.org/10.3389/fimmu.2024.1440269, doi:10.3389/fimmu.2024.1440269. This article has 14 citations and is from a peer-reviewed journal.
(zhang2024newinsightinto pages 12-13): Kangling Zhang, Abhishek Mishra, and Chinnaswamy Jagannath. New insight into arginine and tryptophan metabolism in macrophage activation during tuberculosis. Frontiers in Immunology, Apr 2024. URL: https://doi.org/10.3389/fimmu.2024.1363938, doi:10.3389/fimmu.2024.1363938. This article has 29 citations and is from a peer-reviewed journal.

Citations

chen2024pancanceranalysisof pages 5-10
seo2023immuneregulationthrough pages 4-5
griffith2024thearylhydrocarbon pages 10-12
chen2024pancanceranalysisof pages 14-18
grobben2024targetingaminoacidmetabolizing pages 16-18
grobben2024targetingaminoacidmetabolizing pages 18-19
zhang2024newinsightinto pages 7-8
grobben2024targetingaminoacidmetabolizing pages 29-29
zhang2024newinsightinto pages 12-13
https://doi.org/10.3389/fimmu.2024.1440269;
https://doi.org/10.1038/s12276-023-01028-7
https://doi.org/10.1038/s12276-023-01028-7;
https://doi.org/10.3389/fimmu.2024.1440269
https://doi.org/10.31083/j.rcm2509337;
https://doi.org/10.3389/fimmu.2023.1338244
https://doi.org/10.1007/s12672-024-01000-5;
https://doi.org/10.3389/fphar.2024.1365683
https://doi.org/10.3390/cancers16030472
https://doi.org/10.3390/cancers16030472;
https://doi.org/10.1007/s12672-024-01000-5
https://doi.org/10.3389/fimmu.2024.1440269,
https://doi.org/10.1038/s12276-023-01028-7,
https://doi.org/10.31083/j.rcm2509337,
https://doi.org/10.3389/fimmu.2024.1363938,
https://doi.org/10.3389/fimmu.2023.1338244,
https://doi.org/10.3390/cancers16030472,
https://doi.org/10.1007/s12672-024-01000-5,
https://doi.org/10.3389/fphar.2024.1365683,

📄 View Raw YAML

id: Q96RQ9
gene_symbol: IL4I1
aliases:
- FIG1
- hFIG1
- hIL4I1
- LAAO
- LAO
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
existing_annotations:
- term:
    id: GO:0009063
    label: amino acid catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:17356132
      supporting_text: We showed that IL4I1 has l-amino acid oxidase activity, optimal at physiological pH and primarily directed toward phenylalanine.
    - reference_id: PMID:32818467
      supporting_text: IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid.
    - reference_id: file:human/IL4I1/IL4I1-deep-research-falcon.md
      supporting_text: See deep research file for comprehensive analysis
- term:
    id: GO:0001716
    label: L-amino-acid oxidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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].
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:17356132
      supporting_text: We showed that IL4I1 has l-amino acid oxidase activity, optimal at physiological pH and primarily directed toward phenylalanine.
- term:
    id: GO:0001669
    label: acrosomal vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    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.
    action: ACCEPT
    reason: The electronic annotation is correct and consistent with experimental evidence. IDA annotations for the same term from PMID:25767141 provide direct support.
    supported_by:
    - reference_id: PMID:25767141
      supporting_text: the enzyme was located in the acrosomal region and midpiece of these cells
- term:
    id: GO:0001716
    label: L-amino-acid oxidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    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.
    action: ACCEPT
    reason: Correct electronic annotation for the core molecular function, supported by extensive experimental evidence.
    supported_by:
    - reference_id: PMID:17356132
      supporting_text: We showed that IL4I1 has l-amino acid oxidase activity
- term:
    id: GO:0002250
    label: adaptive immune response
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:17356132
      supporting_text: hIL4I1 inhibited the proliferation of CD3-stimulated T lymphocytes
- term:
    id: GO:0002376
    label: immune system process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: This is a very high-level term that is correct but uninformative. IL4I1 does participate in immune system processes through its immunomodulatory effects.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:17356132
      supporting_text: Altogether these data suggest IL4I1 as a new immunomodulatory enzyme produced by DCs.
- term:
    id: GO:0002841
    label: negative regulation of T cell mediated immune response to tumor cell
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: ACCEPT
    reason: This annotation accurately captures a key immunological function of IL4I1 in tumor biology. Experimental evidence from PMID:32818467 directly supports this term.
    supported_by:
    - reference_id: PMID:32818467
      supporting_text: 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
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    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].
    action: ACCEPT
    reason: Correct electronic annotation supported by multiple IDA annotations. IL4I1 contains a signal peptide and is secreted extracellularly.
    supported_by:
    - reference_id: PMID:17356132
      supporting_text: Both proteins were secreted into the culture medium
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:17356132
      supporting_text: Both proteins were secreted into the culture medium
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    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.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:17356132
      supporting_text: IL4I1 has l-amino acid oxidase activity, optimal at physiological pH
- term:
    id: GO:0009072
    label: aromatic amino acid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:17356132
      supporting_text: We showed that IL4I1 has l-amino acid oxidase activity, optimal at physiological pH and primarily directed toward phenylalanine
    - reference_id: PMID:32818467
      supporting_text: IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid
- term:
    id: GO:0016491
    label: oxidoreductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IL4I1 is an oxidoreductase (L-amino-acid oxidase, EC 1.4.3.2). This term is correct but very general.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:17356132
      supporting_text: We showed that IL4I1 has l-amino acid oxidase activity
- term:
    id: GO:0031410
    label: cytoplasmic vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    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.
    action: ACCEPT
    reason: IL4I1 is present in cytoplasmic vesicles including acrosomal vesicles in sperm. This broader term appropriately captures vesicular localization.
    supported_by:
    - reference_id: PMID:25767141
      supporting_text: the enzyme was located in the acrosomal region and midpiece of these cells
- term:
    id: GO:0045591
    label: positive regulation of regulatory T cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: ARBA annotation supported by experimental evidence from PMID:25778793 demonstrating that IL4I1 promotes FoxP3+ Treg differentiation.
    action: ACCEPT
    reason: Correct annotation with direct experimental support from IDA evidence (PMID:25778793). IL4I1 promotes Treg differentiation through phenylalanine depletion and mTORC1 signaling inhibition.
    supported_by:
    - reference_id: PMID:25778793
      supporting_text: We show that IL4I1 stimulates the generation of Foxp3(+) regulatory T (Treg) cells in vitro from human and mouse T cells
- term:
    id: GO:0106329
    label: L-phenylalaine oxidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  review:
    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.
    action: ACCEPT
    reason: This specific molecular function term accurately captures IL4I1's strongest substrate preference. Phenylalanine is the most efficiently oxidized substrate.
    supported_by:
    - reference_id: PMID:17356132
      supporting_text: We showed that IL4I1 has l-amino acid oxidase activity, optimal at physiological pH and primarily directed toward phenylalanine
    - reference_id: PMID:25778793
      supporting_text: IL4I1 (interleukin-4-induced gene 1) is a phenylalanine oxidase produced mainly by APCs of myeloid origin
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: Interactome maps are valuable resources to elucidate protein function and disease mechanisms
- term:
    id: GO:0001669
    label: acrosomal vesicle
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: This annotation based on immunofluorescence curation aligns with experimental data showing IL4I1 localization to the acrosomal region of human spermatozoa.
    action: ACCEPT
    reason: Immunofluorescence data supports acrosomal localization. Direct experimental evidence from PMID:25767141 confirms this localization.
    supported_by:
    - reference_id: PMID:25767141
      supporting_text: the enzyme was located in the acrosomal region and midpiece of these cells
- term:
    id: GO:0001716
    label: L-amino-acid oxidase activity
  evidence_type: IDA
  original_reference_id: PMID:32866000
  review:
    summary: This study demonstrated IL4I1 can catalyze tryptophan metabolism to produce indole derivatives (IAA, IAld), confirming L-amino acid oxidase activity toward tryptophan.
    action: ACCEPT
    reason: Direct experimental evidence showing IL4I1 oxidizes tryptophan via the indole pyruvate pathway.
    supported_by:
    - reference_id: PMID:32866000
      supporting_text: 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)
- term:
    id: GO:0001669
    label: acrosomal vesicle
  evidence_type: IDA
  original_reference_id: PMID:25767141
  review:
    summary: Houston et al. demonstrated IL4I1 localization to the acrosomal region of human spermatozoa by immunolocalization studies.
    action: ACCEPT
    reason: Direct experimental evidence from immunolocalization studies in human sperm.
    supported_by:
    - reference_id: PMID:25767141
      supporting_text: the enzyme was located in the acrosomal region and midpiece of these cells
- term:
    id: GO:0001716
    label: L-amino-acid oxidase activity
  evidence_type: IDA
  original_reference_id: PMID:17356132
  review:
    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.
    action: ACCEPT
    reason: Core experimental evidence establishing IL4I1 as an L-amino acid oxidase. This paper demonstrated activity in stable cell lines expressing human IL4I1.
    supported_by:
    - reference_id: PMID:17356132
      supporting_text: We showed that IL4I1 has l-amino acid oxidase activity, optimal at physiological pH and primarily directed toward phenylalanine
- term:
    id: GO:0001716
    label: L-amino-acid oxidase activity
  evidence_type: IDA
  original_reference_id: PMID:25767141
  review:
    summary: Houston et al. demonstrated IL4I1 L-amino acid oxidase activity in human spermatozoa with preferred substrates phenylalanine and tryptophan.
    action: ACCEPT
    reason: Independent experimental confirmation of LAAO activity in human sperm, extending the known expression and function context.
    supported_by:
    - reference_id: PMID:25767141
      supporting_text: 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
- term:
    id: GO:0001716
    label: L-amino-acid oxidase activity
  evidence_type: IDA
  original_reference_id: PMID:26673964
  review:
    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.
    action: ACCEPT
    reason: Experimental evidence confirming and extending knowledge of IL4I1 enzymatic activity, including substrate specificity toward arginine.
    supported_by:
    - reference_id: PMID:26673964
      supporting_text: we show that IL4I1 activity is not only directed against phenylalanine, as initially described, but also at a lower level against arginine
- term:
    id: GO:0001716
    label: L-amino-acid oxidase activity
  evidence_type: IDA
  original_reference_id: PMID:32818467
  review:
    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.
    action: ACCEPT
    reason: Key experimental evidence connecting IL4I1 LAAO activity to downstream metabolite production and AHR signaling pathway activation.
    supported_by:
    - reference_id: PMID:32818467
      supporting_text: IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid
- term:
    id: GO:0001772
    label: immunological synapse
  evidence_type: IDA
  original_reference_id: PMID:28891065
  review:
    summary: Aubatin et al. demonstrated focal secretion of IL4I1 into the immune synaptic cleft between APCs and T cells.
    action: ACCEPT
    reason: Direct experimental evidence from imaging studies showing IL4I1 localization at the immunological synapse, where it modulates T cell activation.
    supported_by:
    - reference_id: PMID:28891065
      supporting_text: Focal secretion of IL4I1 into the immune synaptic cleft and its binding to CD3+ lymphocytes could be important in IL4I1 immunosuppressive mechanism of action
- term:
    id: GO:0002819
    label: regulation of adaptive immune response
  evidence_type: IDA
  original_reference_id: PMID:17356132
  review:
    summary: Boulland et al. showed IL4I1 inhibits T cell proliferation, demonstrating its role in regulating adaptive immunity.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0002820
      label: negative regulation of adaptive immune response
    supported_by:
    - reference_id: PMID:17356132
      supporting_text: hIL4I1 inhibited the proliferation of CD3-stimulated T lymphocytes with a similar effect on CD4(+) and CD8(+) T cells
- term:
    id: GO:0002841
    label: negative regulation of T cell mediated immune response to tumor cell
  evidence_type: IDA
  original_reference_id: PMID:32818467
  review:
    summary: Sadik et al. demonstrated IL4I1 suppresses adaptive anti-tumor immunity and promotes tumor progression in experimental models.
    action: ACCEPT
    reason: Direct experimental evidence showing IL4I1 suppresses T cell-mediated anti-tumor immunity, promoting tumor escape.
    supported_by:
    - reference_id: PMID:32818467
      supporting_text: promotes cancer cell motility, and suppresses adaptive immunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL) in mice
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:17356132
  review:
    summary: Boulland et al. demonstrated IL4I1 is secreted into the culture medium, confirming extracellular localization.
    action: ACCEPT
    reason: Direct experimental evidence showing secretion of IL4I1 protein from cells.
    supported_by:
    - reference_id: PMID:17356132
      supporting_text: 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
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:32818467
  review:
    summary: Sadik et al. confirmed IL4I1 secretion and extracellular function in the tumor microenvironment.
    action: ACCEPT
    reason: Additional experimental support for IL4I1 secretion and extracellular activity, consistent with other studies.
    supported_by:
    - reference_id: PMID:32818467
      supporting_text: IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR
- term:
    id: GO:0006559
    label: L-phenylalanine catabolic process
  evidence_type: IDA
  original_reference_id: PMID:17356132
  review:
    summary: IL4I1 catalyzes oxidation of L-phenylalanine to phenylpyruvic acid, representing phenylalanine catabolism.
    action: ACCEPT
    reason: Direct experimental evidence demonstrating phenylalanine as the primary substrate for IL4I1 enzymatic activity.
    supported_by:
    - reference_id: PMID:17356132
      supporting_text: We showed that IL4I1 has l-amino acid oxidase activity, optimal at physiological pH and primarily directed toward phenylalanine
    - reference_id: PMID:25778793
      supporting_text: converts phenylalanine (Phe) to phenylpyruvate, hydrogen peroxide, and ammonia
- term:
    id: GO:0006559
    label: L-phenylalanine catabolic process
  evidence_type: IDA
  original_reference_id: PMID:25767141
  review:
    summary: Houston et al. demonstrated phenylalanine as a preferred substrate for IL4I1 LAAO activity in human spermatozoa.
    action: ACCEPT
    reason: Independent confirmation of phenylalanine catabolism in a different cellular context (sperm).
    supported_by:
    - reference_id: PMID:25767141
      supporting_text: The preferred substrates were found to be phenylalanine and tryptophan
- term:
    id: GO:0006569
    label: L-tryptophan catabolic process
  evidence_type: IDA
  original_reference_id: PMID:17356132
  review:
    summary: IL4I1 oxidizes tryptophan to indole-3-pyruvic acid as part of its LAAO activity.
    action: ACCEPT
    reason: Experimental evidence supports tryptophan as a substrate, though with lower preference than phenylalanine.
    supported_by:
    - reference_id: PMID:17356132
      supporting_text: We showed that IL4I1 has l-amino acid oxidase activity
- term:
    id: GO:0006569
    label: L-tryptophan catabolic process
  evidence_type: IDA
  original_reference_id: PMID:25767141
  review:
    summary: Houston et al. confirmed tryptophan as a substrate for IL4I1 in sperm.
    action: ACCEPT
    reason: Direct experimental evidence for tryptophan oxidation by IL4I1.
    supported_by:
    - reference_id: PMID:25767141
      supporting_text: The preferred substrates were found to be phenylalanine and tryptophan
- term:
    id: GO:0006572
    label: L-tyrosine catabolic process
  evidence_type: IDA
  original_reference_id: PMID:17356132
  review:
    summary: IL4I1 oxidizes tyrosine to 4-hydroxyphenylpyruvic acid as part of its broad aromatic amino acid oxidase activity.
    action: ACCEPT
    reason: Experimental evidence supports tyrosine catabolism by IL4I1, consistent with its activity on aromatic amino acids.
    supported_by:
    - reference_id: PMID:32818467
      supporting_text: IL4I1 activates the AHR through the generation of indole metabolites
- term:
    id: GO:0019440
    label: obsolete L-tryptophan catabolic process to indole-3-acetate
  evidence_type: IDA
  original_reference_id: PMID:32818467
  review:
    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.
    action: ACCEPT
    reason: Key finding establishing IL4I1's role in the indole pyruvate pathway for tryptophan metabolism, distinct from the kynurenine pathway.
    supported_by:
    - reference_id: PMID:32818467
      supporting_text: IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid
- term:
    id: GO:0019440
    label: obsolete L-tryptophan catabolic process to indole-3-acetate
  evidence_type: IDA
  original_reference_id: PMID:32866000
  review:
    summary: Zhang et al. directly demonstrated IL4I1 produces indole-3-acetic acid (IAA) from tryptophan via the indole pyruvate pathway.
    action: ACCEPT
    reason: Direct experimental evidence showing IL4I1-mediated production of IAA from tryptophan in an overexpression cell model.
    supported_by:
    - reference_id: PMID:32866000
      supporting_text: 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)
- term:
    id: GO:0042130
    label: negative regulation of T cell proliferation
  evidence_type: IMP
  original_reference_id: PMID:17356132
  review:
    summary: Boulland et al. demonstrated IL4I1 inhibits T cell proliferation through enzymatic activity-dependent H2O2 production. Mutagenesis of the catalytic glutamate (E481A) abolished activity.
    action: ACCEPT
    reason: Key experimental finding establishing IL4I1's immunosuppressive function. The effect was shown to be dependent on enzymatic activity and H2O2 production.
    supported_by:
    - reference_id: PMID:17356132
      supporting_text: 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
- term:
    id: GO:0045577
    label: regulation of B cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    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.
    action: UNDECIDED
    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.
    supported_by:
    - reference_id: PMID:17356132
      supporting_text: Interleukin-4-induced gene 1 (IL4I1) was first described as a B-cell IL4-inducible gene
- term:
    id: GO:0045591
    label: positive regulation of regulatory T cell differentiation
  evidence_type: IDA
  original_reference_id: PMID:25778793
  review:
    summary: Cousin et al. demonstrated IL4I1 promotes FoxP3+ Treg differentiation through phenylalanine depletion and mTORC1 signaling inhibition.
    action: ACCEPT
    reason: Direct experimental evidence showing IL4I1 stimulates Treg generation in vitro from both human and mouse T cells.
    supported_by:
    - reference_id: PMID:25778793
      supporting_text: We show that IL4I1 stimulates the generation of Foxp3(+) regulatory T (Treg) cells in vitro from human and mouse T cells
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:32818467
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0032089
      label: negative regulation of cellular response to stimulus
    - id: GO:0010467
      label: gene expression
    additional_reference_ids:
    - PMID:32866000
    supported_by:
    - reference_id: PMID:32818467
      supporting_text: IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid
    - reference_id: PMID:32866000
      supporting_text: both IAA and IAld are accumulated in dendritic cells (DCs) and can stimulate the expression of CYP1A1
- term:
    id: GO:0050868
    label: negative regulation of T cell activation
  evidence_type: IDA
  original_reference_id: PMID:28891065
  review:
    summary: Aubatin et al. demonstrated IL4I1 decreases early signaling events downstream of TCR stimulation, resulting in T cell inhibition.
    action: ACCEPT
    reason: Direct experimental evidence showing IL4I1 suppresses T cell activation through effects on TCR signaling.
    supported_by:
    - reference_id: PMID:28891065
      supporting_text: the presence of IL4I1 during T-cell activation decreases early signaling events downstream of TCR stimulation, resulting in global T-cell inhibition
- term:
    id: GO:0097225
    label: sperm midpiece
  evidence_type: IDA
  original_reference_id: PMID:25767141
  review:
    summary: Houston et al. localized IL4I1 to the midpiece of human spermatozoa in addition to the acrosomal region.
    action: ACCEPT
    reason: Direct experimental evidence from immunolocalization studies showing IL4I1 presence in the sperm midpiece.
    supported_by:
    - reference_id: PMID:25767141
      supporting_text: the enzyme was located in the acrosomal region and midpiece of these cells
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2160492
  review:
    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.
    action: ACCEPT
    reason: Consistent with multiple experimental studies showing IL4I1 secretion. Reactome annotation reflects established knowledge of IL4I1 localization.
    supported_by:
    - reference_id: PMID:17356132
      supporting_text: Both proteins were secreted into the culture medium
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:17356132
  title: Human IL4I1 is a secreted L-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation.
  findings:
  - statement: IL4I1 has L-amino acid oxidase activity, primarily toward phenylalanine
    supporting_text: We showed that IL4I1 has l-amino acid oxidase activity, optimal at physiological pH and primarily directed toward phenylalanine.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: IL4I1 is secreted into extracellular medium
    supporting_text: 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, MedB-1.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: IL4I1 inhibits T cell proliferation via H2O2 production
    supporting_text: hIL4I1 inhibited the proliferation of CD3-stimulated T lymphocytes with a similar effect on CD4(+) and CD8(+) T cells. In contrast, memory T cells were more strongly affected by hIL4I1 and its catabolite H(2)O(2) than naive T cells. hIL4I1 inhibitory effect was dependent on enzymatic activity and H(2)O(2) production
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: Expressed by mature dendritic cells and macrophages
    supporting_text: Immunohistochemical analysis of secondary lymphoid organs showed staining of germinal center macrophages and inflammatory myeloid cells. In vitro, functional enzyme was highest in mature dendritic cells (DCs), suggesting a role in antigen-presenting cell/T-lymphocyte cross-talk.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
- id: PMID:25767141
  title: Human spermatozoa possess an IL4I1 l-amino acid oxidase with a potential role in sperm function.
  findings:
  - statement: IL4I1 is present in human spermatozoa
    supporting_text: 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 in the presence of oxygen.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: Localized to acrosomal region and midpiece
    supporting_text: the enzyme was located in the acrosomal region and midpiece of these cells.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: Preferred substrates are phenylalanine and tryptophan
    supporting_text: The preferred substrates were found to be phenylalanine and tryptophan
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: May regulate capacitation and acrosomal exocytosis
    supporting_text: Stimulation of LAAO activity resulted in the induction of several hallmarks of capacitation including tyrosine phosphorylation of the sperm flagellum and concomitant activation of phospho-SRC expression. In addition, stimulation of LAAO resulted in an increase in the levels of acrosomal exocytosis in both the presence and absence of progesterone stimulation
    reference_section_type: ABSTRACT
    full_text_unavailable: true
- id: PMID:25778793
  title: The immunosuppressive enzyme IL4I1 promotes FoxP3(+) regulatory T lymphocyte differentiation.
  findings:
  - statement: IL4I1 promotes FoxP3+ Treg differentiation
    supporting_text: We show that IL4I1 stimulates the generation of Foxp3(+) regulatory T (Treg) cells in vitro from human and mouse T cells.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: Effect mediated through phenylalanine consumption and mTORC1 inhibition
    supporting_text: Analysis of Treg-cell induction under conditions of Phe deprivation and hydrogen peroxide addition suggests that Phe consumption by the enzyme participates in Treg-cell enrichment. In line with this hypothesis, IL4I1 inhibits mTORC1 signaling shortly after T-cell activation.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: IL4I1 limits Th1 and Th2 polarization
    supporting_text: Conversely, IL4I1 limits Th1 and Th2 polarization while modifying the Th17 phenotype, in particular, by inducing its own production.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
- id: PMID:26673964
  title: Alterations of the immunosuppressive IL4I1 enzyme activity induced by naturally occurring SNP/mutations.
  findings:
  - statement: IL4I1 also has weak activity against L-arginine
    supporting_text: we show that IL4I1 activity is not only directed against phenylalanine, as initially described, but also at a lower level against arginine.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: Natural SNPs can alter enzyme activity (N92D hyperactive, R102G hypomorphic)
    supporting_text: The N92D SNP leads to a hyperactive enzyme, while the R102G mutation is hypomorphic.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
- id: PMID:28891065
  title: IL4-induced gene 1 is secreted at the immune synapse and modulates TCR activation independently of its enzymatic activity.
  findings:
  - statement: IL4I1 is secreted at the immunological synapse
    supporting_text: Focal secretion of IL4I1 into the immune synaptic cleft and its binding to CD3+ lymphocytes could be important in IL4I1 immunosuppressive mechanism of action.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: Decreases TCR signaling events
    supporting_text: the presence of IL4I1 during T-cell activation decreases early signaling events downstream of TCR stimulation, resulting in global T-cell inhibition which is more pronounced when there is CD28 costimulation.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: Some effects independent of enzymatic activity
    supporting_text: Surprisingly, the enzymatic activity of IL4I1 is not involved.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings:
  - statement: High-throughput Y2H interactome screen
    supporting_text: Here, we report on an interactome map that focuses on neurodegenerative disease (ND), connects ∼5,000 human proteins via ∼30,000 candidate interactions and is generated by systematic yeast two-hybrid interaction screening of ∼500 ND-related proteins and integration of literature interactions.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: IL4I1 identified in network but not primary focus of study
    supporting_text: Interactome maps are valuable resources to elucidate protein function and disease mechanisms.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
- id: PMID:32818467
  title: IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression.
  findings:
  - statement: IL4I1 activates AHR through indole metabolites and kynurenic acid
    supporting_text: IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: Suppresses anti-tumor immunity
    supporting_text: suppresses adaptive immunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL) in mice.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: Promotes tumor progression
    supporting_text: promotes cancer cell motility, and suppresses adaptive immunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL) in mice.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: Associates with poor prognosis in glioma
    supporting_text: It associates with reduced survival in glioma patients
    reference_section_type: ABSTRACT
    full_text_unavailable: true
- id: PMID:32866000
  title: Endogenous Indole Pyruvate Pathway for Tryptophan Metabolism Mediated by IL4I1.
  findings:
  - statement: IL4I1 catalyzes Trp to IAA and IAld production
    supporting_text: 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).
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: Establishes endogenous indole pyruvate pathway in host cells
    supporting_text: Our results demonstrate the existence of the indole pyruvate pathway in host cells with IL4I1 as the key enzyme.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: Products activate AHR through CYP1A1 expression
    supporting_text: both IAA and IAld are accumulated in dendritic cells (DCs) and can stimulate the expression of CYP1A1.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
- id: Reactome:R-HSA-2160492
  title: IL4I1:FAD oxidises L-Phe to kPPV
  findings:
  - statement: Reactome pathway annotation for phenylalanine metabolism
    supporting_text: Extracellular L-amino-acid oxidase (IL4I1) catalyzes the reaction of phenylalanine, water, and molecular oxygen to form keto-phenylpyruvate, ammonia, and hydrogen peroxide. IL4I1, inferred to form a complex with FAD, has L-amino acid oxidase activity and with a strong preference for phenylalanine.
    reference_section_type: ABSTRACT
    full_text_unavailable: false
- id: file:human/IL4I1/IL4I1-deep-research-falcon.md
  title: Deep research on IL4I1 function
  findings: []
core_functions:
- description: 'IL4I1 is an FAD-dependent L-amino acid oxidase (EC 1.4.3.2, EC 1.4.3.25) that catalyzes the oxidative deamination of L-amino acids to alpha-keto acids with production of hydrogen peroxide and ammonia. Primary substrates are aromatic amino acids: phenylalanine (highest activity), tyrosine, and tryptophan. Weak activity against L-arginine has also been demonstrated. This enzymatic activity underlies all of IL4I1''s biological functions.'
  molecular_function:
    id: GO:0001716
    label: L-amino-acid oxidase activity
  supported_by:
  - reference_id: PMID:17356132
    supporting_text: We showed that IL4I1 has l-amino acid oxidase activity, optimal at physiological pH and primarily directed toward phenylalanine.
  - reference_id: PMID:25767141
    supporting_text: The preferred substrates were found to be phenylalanine and tryptophan
  - reference_id: PMID:26673964
    supporting_text: we show that IL4I1 activity is not only directed against phenylalanine, as initially described, but also at a lower level against arginine
- description: IL4I1 mediates an endogenous indole pyruvate pathway for tryptophan metabolism, converting Trp to indole-3-pyruvic acid (I3P), which gives rise to indole-3-acetic acid (IAA), indole-3-aldehyde (I3A), and kynurenic acid. These metabolites are potent aryl hydrocarbon receptor (AHR) agonists, linking IL4I1 enzymatic activity to immunomodulation and tumor biology.
  molecular_function:
    id: GO:0001716
    label: L-amino-acid oxidase activity
  directly_involved_in:
  - id: GO:0006569
    label: L-tryptophan catabolic process
  supported_by:
  - reference_id: PMID:32818467
    supporting_text: IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid
  - reference_id: PMID:32866000
    supporting_text: 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)
- description: IL4I1 inhibits T cell proliferation through H2O2 production (dependent on enzymatic activity) and phenylalanine depletion affecting mTORC1 signaling. This immunosuppressive function is central to IL4I1's role in adaptive immunity and tumor immune evasion.
  molecular_function:
    id: GO:0001716
    label: L-amino-acid oxidase activity
  directly_involved_in:
  - id: GO:0042130
    label: negative regulation of T cell proliferation
  supported_by:
  - reference_id: PMID:17356132
    supporting_text: 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
  - reference_id: PMID:25778793
    supporting_text: IL4I1 inhibits T-cell proliferation via hydrogen peroxide toxicity on effector/memory T cells
- description: IL4I1 promotes FoxP3+ regulatory T cell differentiation through phenylalanine consumption and mTORC1 signaling inhibition. This contributes to the overall immunosuppressive phenotype induced by IL4I1 expression.
  molecular_function:
    id: GO:0001716
    label: L-amino-acid oxidase activity
  directly_involved_in:
  - id: GO:0045591
    label: positive regulation of regulatory T cell differentiation
  supported_by:
  - reference_id: PMID:25778793
    supporting_text: We show that IL4I1 stimulates the generation of Foxp3(+) regulatory T (Treg) cells in vitro from human and mouse T cells
proposed_new_terms: []
suggested_questions:
- question: 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.
- question: 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.
suggested_experiments:
- description: Test whether IL4I1 knockout or inhibition affects anti-tumor T cell responses in human tumor microenvironment models to validate the metabolic checkpoint function.
- description: Determine whether IL4I1 localizes to and functions at the immunological synapse in vivo, and whether AHR activation occurs locally at the synapse.

Gene Description

Existing Annotations Review

Core Functions

IL4I1 inhibits T cell proliferation through H2O2 production (dependent on enzymatic activity) and phenylalanine depletion affecting mTORC1 signaling. This immunosuppressive function is central to IL4I1's role in adaptive immunity and tumor immune evasion.

IL4I1 promotes FoxP3+ regulatory T cell differentiation through phenylalanine consumption and mTORC1 signaling inhibition. This contributes to the overall immunosuppressive phenotype induced by IL4I1 expression.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Citations

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