title: Proteasomal Degradation of Indoleamine 2,3-Dioxygenase in CD8 Dendritic Cells is Mediated by Suppressor of Cytokine Signaling 3 (SOCS3).
abstract: Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial and rate-limiting step of tryptophan catabolism in a specific pathway, resulting in a series of extracellular messengers collectively known as kynurenines. IDO has been recognized as an authentic regulator of immunity not only in mammalian pregnancy, but also in infection, autoimmunity, inflammation, allergy, transplantation, and neoplasia. Its suppressive effects are mostly mediated by dendritic cells (DCs) and involve tryptophan deprivation and/or production of kynurenines, which act on IDO-negative DCs as well as CD4(+) and CD8(+) T cells. We have found that mouse IDO contains two tyrosine residues within two distinct putative immunoreceptor tyrosine-based inhibitory motifs, VPY(115)CEL and LLY(253)EGV. We have also found that Suppressor of Cytokine Signaling 3 (SOCS3)-known to interact with phosphotyrosine-containing peptides and be selectively induced by interleukin 6 (IL-6)-binds mouse IDO, recruits the ECS (Elongin-Cullin-SOCS) E3 ligase, and targets the IDO/SOCS3 complex for proteasomal degradation. This event underlies the ability of IL-6 to convert otherwise tolerogenic, IDO-competent DCs into immunogenic cells. Thus onset of immunity in response to antigen within an early inflammatory context demands that IDO be degraded in tolerogenic DCs. These studies support the finding that IDO is regulated by proteasomal degradation in response to immunogenic and inflammatory stimuli.
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06126 Perugia, Italy.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Pallotta
authors.forename: Ciriana
authors.initials: C
authors.lastname: Orabona
authors.forename: Claudia
authors.initials: C
authors.lastname: Volpi
authors.forename: Ursula
authors.initials: U
authors.lastname: Grohmann
authors.forename: Paolo
authors.initials: P
authors.lastname: Puccetti
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
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