Indoleamine 2,3-dioxygenase 1 (IDO1): an up-to-date overview of an eclectic immunoregulatory enzyme

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the initial rate-limiting step in the degradation of the essential amino acid tryptophan along the kynurenine pathway. When discovered more than 50 years ago, IDO1 was thought to be an effector molecule capable of mediating a survival strategy based on the deprivation of bacteria and tumor cells of the essential amino acid tryptophan. Since 1998, when tryptophan catabolism was discovered to be crucially involved in the maintenance of maternal T-cell tolerance, IDO1 has become the focus of several laboratories around the world. Indeed, IDO1 is now considered as an authentic immune regulator not only in pregnancy, but also in autoimmune diseases, chronic inflammation, and tumor immunity. However, in the last years, a bulk of new information-including structural, biological, and functional evidence-on IDO1 has come to light. For instance, we now know that IDO1 has a peculiar conformational plasticity and, in addition to a complex and highly regulated catalytic activity, is capable of performing a nonenzymic function that reprograms the expression profile of immune cells toward a highly immunoregulatory phenotype. With this state-of-the-art review, we aimed at gathering the most recent information obtained for this eclectic protein as well as at highlighting the major unresolved questions.

Keywords: Src kinase; dendritic cells; early endosomes; indoleamine 2,3-dioxygenase 1; moonlighting protein; phosphatidylinositol 3-kinase; tryptophan metabolism.

Fig. 1

The KP in mammals. The first and rate‐limiting step in the KP is catalyzed by IDO1, IDO2, and TDO. N‐formylkynurenine is rapidly metabolized by AFMID into l‐kynurenine, which can be transformed by KATs, KYNU, and KMO into kynurenic acid, anthranilic acid, and 3‐hydroxykynurenine, respectively. 3‐hydroxykynurenine can be then transformed by KATs into xanthurenic acid or KYNU into 3‐hydroxyanthranilic acid, which can be converted by 3‐HAO into 2‐amino‐3‐carboxymuconic‐6‐semialdehyde that spontaneously transforms into quinolinic acid. NAD⁺, the final product of the pathway, is then obtained by several enzymatic reactions. IDO1, indoleamine 2,3‐dioxygenase 1; TDO, tryptophan dioxygenase; IDO2, indoleamine 2,3‐dioxygenase 2; AFMID, kynurenine formamidase; KATs, kynurenine aminotransferases; KYNU, kynureninase; KMO, kynurenine monooxygenase; 3‐HAO, 3‐hydroxyamino oxidase; NAD+, nicotinamide adenine dinucleotide; QPRT, quinolinate phosphoribosyltransferase.

Fig. 2

Crystal structure of substrate‐bound IDO1 (pdb code: 5WMU). Key structural elements are highlighted and labeled: ITIMs (Tyr111, Tyr249, orange CPK atoms); YENM motif (orange CPK atom sticks); narrow channel (cyan surface). Heme cofactor (green carbon atoms) and l‐Trp (orange carbon atom sticks).

Fig. 3

Binding mode of l‐Trp (orange carbon atom sticks) into the catalytic site of IDO1 (pdb code: 5WMU). Hydrogen bond interactions between l‐Trp and binding site residues are shown in black dashed lines. The EF loop is highlighted with a purple cartoon.

Fig. 4

Binding mode of l‐Trp (orange carbon atom sticks) into the accessory site of the Phe270Gly variant of IDO1 (pdb code: 5WMW). l‐Trp engages a cluster of nonpolar residues (Val170, Val269, Leu342) in hydrophobic contacts, whereas no polar interactions are observed.

Fig. 5

Intracellular dynamics of IDO1 in DCs. Depending on the microenvironment, IDO1 shapes its conformation and acquires functions suitable for cellular needs. (A) In acute inflammation, the pro‐inflammatory cytokine IFN‐γ induces IDO1 enzymic activity, promoting transformation of l‐Trp into l‐Kyn, an agonist of AhR, a ligand‐activated transcription factor that moves from cytosol to the nucleus and, via a positive feedback loop, upregulates Ido1 gene expression. (B) Pro‐inflammatory contexts driven by IL‐6 are characterized by the upregulation of SOCS3, which associates with phosphorylated ITIM2 via its SH2 domain, recruits the E3 ubiquitin ligase complex, and directs cytosolic IDO1 to proteasomal degradation. (C) In a microenvironment dominated by immunoregulatory TGF‐β, IDO1 is phosphorylated in ITIM (ITIM1 and ITIM2) and YENM domains, which bind and activate SHPs and PI3Ks, respectively. PI3K activation implies IDO1 direct binding to the p85 regulatory subunit that in turn promotes activation of p110, the PI3K catalytic subunit. PI3K binding favors IDO1 anchoring to EE and signaling function. SHP binding promotes IKKα‐dependent activation of the noncanonical pathway of NF‐κB that, via the p52/RelB heterodimer translocating to the nucleus, upregulates the expression of Ido1 and Tgfb1 genes. This mechanism establishes a positive immunoregulatory circuitry that ensures IDO1 long‐term expression in dendritic cells. IDO1, indoleamine 2,3‐dioxygenase 1; IFN‐γ, interferon γ; l‐Trp, l‐tryptophan; l‐Kyn, l‐kynurenine; AhR, aryl hydrocarbon receptor; IL‐6, interleukin‐6; SOCS3, suppressor of cytokine signaling 3; ITIM, immune tyrosine‐based inhibitory motif; TGF‐β, transforming growth factor β; PI3Ks, phosphoinositide 3‐kinases; EE, early endosome; SHPs, Src homology 2 domain phosphatases; IKKα, inhibitory‐κB kinase α.