Class IA PI3Ks regulate subcellular and functional dynamics of IDO1

none35sìKnowledge of a protein's spatial dynamics at the subcellular level is key to understanding its function(s), interactions, and associated intracellular events. Indoleamine 2,3-dioxygenase 1 (IDO1) is a cytosolic enzyme that controls immune responses via tryptophan metabolism, mainly through its enzymic activity. When phosphorylated, however, IDO1 acts as a signaling molecule in plasmacytoid dendritic cells (pDCs), thus activating genomic effects, ultimately leading to long-lasting immunosuppression. Whether the two activities-namely, the catalytic and signaling functions-are spatially segregated has been unclear. We found that, under conditions favoring signaling rather than catabolic events, IDO1 shifts from the cytosol to early endosomes. The event requires interaction with class IA phosphoinositide 3-kinases (PI3Ks), which become activated, resulting in full expression of the immunoregulatory phenotype in vivo in pDCs as resulting from IDO1-dependent signaling events. Thus, IDO1's spatial dynamics meet the needs for short-acting as well as durable mechanisms of immune suppression, both under acute and chronic inflammatory conditions. These data expand the theoretical basis for an IDO1-centered therapy in inflammation and autoimmunity.noneAlberta Iacono , Andrea Pompa, Francesca De Marchis , Eleonora Panfili , Francesco A Greco , Alice Coletti , Ciriana Orabona , Claudia Volpi , Maria L Belladonna , Giada Mondanelli, Elisa Albini , Carmine Vacca , Marco Gargaro , Francesca Fallarino , Roberta Bianchi , Carine De Marcos Lousa , Emilia Mc Mazza , Silvio Bicciato , Elisa Proietti , Francesca Milano , Maria P Martelli , Ioana M Iamandii , Mariona Graupera Garcia-Mila , Judith Llena Sopena , Phillip Hawkins , Sabine Suire , Klaus Okkenhaug , Anne-Katrien Stark , Fabio Grassi , Michele Bellucci , Paolo Puccetti , Laura Santambrogio , Antonio Macchiarulo, Ursula Grohmann , Maria T PallottaIacono, Alberta; Pompa, Andrea; De Marchis, Francesca; Panfili, Eleonora; A Greco, Francesco; Coletti, Alice; Orabona, Ciriana; Volpi, Claudia; L Belladonna, Maria; Mondanelli, Giada; Albini, Elisa; Vacca, Carmine; Gargaro, Marco; Fallarino, Francesca; Bianchi, Roberta; De Marcos Lousa, Carine; Mc Mazza, Emilia; Bicciato, Silvio; Proietti, Elisa; Milano, Francesca; P Martelli, Maria; M Iamandii, Ioana; Graupera Garcia-Mila, Mariona; Llena Sopena, Judith; Hawkins, Phillip; Suire, Sabine; Okkenhaug, Klaus; Stark, Anne-Katrien; Grassi, Fabio; Bellucci, Michele; Puccetti, Paolo; Santambrogio, Laura; Macchiarulo, Antonio; Grohmann, Ursula; T Pallotta, Mari