ArticleJournal of cellular and molecular medicine2017
Distinct roles of immunoreceptor tyrosine-based motifs in immunosuppressive indoleamine 2,3-dioxygenase 1.
Article in Journal of cellular and molecular medicine, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 70 citations in OpenAlex.
- HCellular & molecular biology letters · 2026Article
- Phosphatases in tumor cell immune escape: a perspective based on the camouflage, coercion, cytoprotection.Frontiers in cell and developmental biology · 2026Review
- Ido1 or Ido2 deficiency in myeloid-derived cells attenuates TMEV-induced ictogenesis.Journal of neuroimmunology · 2025Article
- Microglia-specific Ido2 deficiency attenuates ictogenesis in the TMEV model of viral encephalitis.Brain, behavior, and immunity · 2025Article
- SOCS3: An Immunological Biomarker Offering Potential Therapeutic Targets for Malignant Tumors.Biological procedures online · 2025Review
- Phosphorylation of ITIM motifs drives the structural transition of indoleamine 2,3-dioxygenase 1 between enzymatic and non-enzymatic states.Protein science : a publication of the Protein Society · 2025Article
- Radiation-Enhanced AF1q Moves Center Stage as a Key Driver to Favorable Tumor Stage in Rectal Cancer Patients.Cancer medicine · 2025Article
- The Kynurenine Pathway and Indole Pathway in Tryptophan Metabolism Influence Tumor Progression.Cancer medicine · 2025Review
- IDO and TDO inhibitors in cancer immunotherapy: mechanisms, clinical development, and future directions.Frontiers in pharmacology · 2025Review
- Adverse pro-tumorigenic effects of IDO1 catalytic inhibitors mediated by the non-enzymatic function of IDO1 in tumor cells.Frontiers in immunology · 2025Article
- Emerging roles of metabolic biomarkers in renal cell carcinoma: from molecular mechanisms to clinical implications.Frontiers in cell and developmental biology · 2025Review
- Low Indoleamine 2,3-Dioxygenase 1 Expression Enhances Dendritic Cells Response to Tumor Cells Against Hepatocellular Carcinoma.Journal of hepatocellular carcinoma · 2025Article
- Review
- Identification of a Compound Inhibiting Both the Enzymatic and Nonenzymatic Functions of Indoleamine 2,3-Dioxygenase 1.ACS pharmacology & translational science · 2024Article
- Epacadostat stabilizes the apo-form of IDO1 and signals a pro-tumorigenic pathway in human ovarian cancer cells.Frontiers in immunology · 2024Article
- Membrane Localization and Phosphorylation of Indoleamine 2,3-Dioxygenase 2 (IDO2) in A549 Human Lung Adenocarcinoma Cells: First Steps in Exploring Its Signaling Function.International journal of molecular sciences · 2023Article
- A back-door insight into the modulation of Src kinase activity by the polyamine spermidine.eLife · 2023Article
- The signaling function of IDO1 incites the malignant progression of mouse B16 melanoma.Oncoimmunology · 2023Article
- The catalytic inhibitor epacadostat can affect the non-enzymatic function of IDO1.Frontiers in immunology · 2023Article
- Structure-based optimization of type III indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2022Article
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Authors and funding
15 authors at 1 institution in 1 country.
Funding
Abstract
The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) catalyses the initial, rate-limiting step in tryptophan (Trp) degradation, resulting in tryptophan starvation and the production of immunoregulatory kynurenines. IDO1's catalytic function has long been considered as the one mechanism responsible for IDO1-dependent immune suppression by dendritic cells (DCs), which are master regulators of the balance between immunity and tolerance. However, IDO1 also harbours immunoreceptor tyrosine-based inhibitory motifs, (ITIM1 and ITIM2), that, once phosphorylated, bind protein tyrosine phosphatases, (SHP-1 and SHP-2), and thus trigger an immunoregulatory signalling in DCs. This mechanism leads to sustained IDO1 expression, in a feedforward loop, which is particularly important in restraining autoimmunity and chronic inflammation. Yet, under specific conditions requiring that early and protective inflammation be unrelieved, tyrosine-phosphorylated ITIMs will instead bind the suppressor of cytokine signalling 3 (SOCS3), which drives IDO1 proteasomal degradation and shortens the enzyme half-life. To dissect any differential roles of the two IDO1's ITIMs, we generated protein mutants by replacing one or both ITIM-associated tyrosines with phospho-mimicking glutamic acid residues. Although all mutants lost their enzymic activity, the ITIM1 - but not ITIM2 mutant - did bind SHPs and conferred immunosuppressive effects on DCs, making cells capable of restraining an antigen-specific response in vivo. Conversely, the ITIM2 mutant would preferentially bind SOCS3, and IDO1's degradation was accelerated. Thus, it is the selective phosphorylation of either ITIM that controls the duration of IDO1 expression and function, in that it dictates whether enhanced tolerogenic signalling or shutdown of IDO1-dependent events will occur in a local microenvironment.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.