2. Academic Validation
  3. Class IA PI3Ks regulate subcellular and functional dynamics of IDO1

Class IA PI3Ks regulate subcellular and functional dynamics of IDO1

  • EMBO Rep. 2020 Dec 3;21(12):e49756. doi: 10.15252/embr.201949756.
Alberta Iacono 1,  Andrea Pompa 2 3,  Francesca De Marchis 3,  Eleonora Panfili 1,  Francesco A Greco 4,  Alice Coletti 4,  Ciriana Orabona 1,  Claudia Volpi 1,  Maria L Belladonna 1,  Giada Mondanelli,  Elisa Albini 1 4,  Carmine Vacca 1,  Marco Gargaro 1,  Francesca Fallarino 1,  Roberta Bianchi 1,  Carine De Marcos Lousa 5 6,  Emilia Mc Mazza 7,  Silvio Bicciato 8,  Elisa Proietti 1,  Francesca Milano 9,  Maria P Martelli 9,  Ioana M Iamandii 1,  Mariona Graupera Garcia-Mila 10,  Judith Llena Sopena 10,  Phillip Hawkins 11,  Sabine Suire 11,  Klaus Okkenhaug 12,  Anne-Katrien Stark 12,  Fabio Grassi 13,  Michele Bellucci 3,  Paolo Puccetti 1,  Laura Santambrogio 14,  Antonio Macchiarulo 4,  Ursula Grohmann 1 15,  Maria T Pallotta 1
Affiliations

Affiliations

  • 1 Department of Experimental Medicine, University of Perugia, Perugia, Italy.
  • 2 Department of Biomolecular Sciences, University Carlo Bo, Urbino, Italy.
  • 3 Institute of Biosciences and Bioresources, National Research Council of Italy, Perugia, Italy.
  • 4 Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy.
  • 5 Centre for Biomedical Sciences, School of Clinical and Applied Sciences, Leeds Beckett University, Leeds, UK.
  • 6 Center for Plant Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, UK.
  • 7 Istituto Clinico Humanitas, Rozzano, Italy.
  • 8 Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  • 9 Department of Medicine, University of Perugia, Perugia, Italy.
  • 10 Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Spain.
  • 11 Babraham Institute, Cambridge, UK.
  • 12 Department of Pathology, University of Cambridge, Cambridge, UK.
  • 13 Institute for Research in Biomedicine, Bellinzona, Switzerland.
  • 14 Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.
  • 15 Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
PMID: 33159421 DOI: 10.15252/embr.201949756
Abstract

Knowledge 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.

Keywords

dendritic cells; early endosomes; indoleamine 2,3-dioxygenase 1 (IDO1); phosphoinositide 3-kinase (PI3K); tryptophan metabolism.

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