title: Spatiotemporal control of interferon-induced JAK/STAT signalling and gene transcription by the retromer complex.
abstract: Type-I interferons (IFNs) play a key role in the immune defences against viral and bacterial infections, and in cancer immunosurveillance. We have established that clathrin-dependent endocytosis of the type-I interferon (IFN-α/β) receptor (IFNAR) is required for JAK/STAT signalling. Here we show that the internalized IFNAR1 and IFNAR2 subunits of the IFNAR complex are differentially sorted by the retromer at the early endosome. Binding of the retromer VPS35 subunit to IFNAR2 results in IFNAR2 recycling to the plasma membrane, whereas IFNAR1 is sorted to the lysosome for degradation. Depletion of VPS35 leads to abnormally prolonged residency and association of the IFNAR subunits at the early endosome, resulting in increased activation of STAT1- and IFN-dependent gene transcription. These experimental data establish the retromer complex as a key spatiotemporal regulator of IFNAR endosomal sorting and a new factor in type-I IFN-induced JAK/STAT signalling and gene transcription.
authors.affiliation: Membrane Dynamics and Mechanics of Intracellular Signaling Laboratory, Institut Curie-Centre de Recherche, PSL Research University, 26 rue d'Ulm, F-75248 Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) U1143, 75005 Paris, France.|Centre National de la Recherche Scientifique (CNRS), UMR 3666, 75005 Paris, France.
authors.forename: Daniela
authors.initials: D
authors.lastname: Chmiest
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Nanaocha
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Membrane Dynamics and Mechanics of Intracellular Signaling Laboratory, Institut Curie-Centre de Recherche, PSL Research University, 26 rue d'Ulm, F-75248 Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) U1143, 75005 Paris, France.|Centre National de la Recherche Scientifique (CNRS), UMR 3666, 75005 Paris, France.
authors.forename: Natacha
authors.initials: N
authors.lastname: Zanin
authors.affiliation: Membrane Dynamics and Mechanics of Intracellular Signaling Laboratory, Institut Curie-Centre de Recherche, PSL Research University, 26 rue d'Ulm, F-75248 Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) U1143, 75005 Paris, France.|Centre National de la Recherche Scientifique (CNRS), UMR 3666, 75005 Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Viaris de Lesegno
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1143, 75005 Paris, France.|Centre National de la Recherche Scientifique (CNRS), UMR 3666, 75005 Paris, France.|Endocytic Trafficking and Intracellular Delivery Laboratory, Institut Curie-Centre de Recherche, PSL Research University, F-75248 Paris, France.
authors.forename: Massiullah
authors.initials: M
authors.lastname: Shafaq-Zadah
authors.affiliation: Bioinformatics and Computational Systems Biology of Cancer, Institut Curie-Centre de Recherche, PSL Research University, F-75248 Paris, France.|INSERM U900, 75005 Paris, France.|Mines Paris-Tech, F-75272 Paris, France.
authors.forename: Vonick
authors.initials: V
authors.lastname: Sibut
authors.affiliation: Proteomics and Mass Spectrometry Laboratory, Institut Curie-Centre de Recherche, PSL Research University, F-75248 Paris, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Dingli
authors.affiliation: Bioinformatics and Computational Systems Biology of Cancer, Institut Curie-Centre de Recherche, PSL Research University, F-75248 Paris, France.|INSERM U900, 75005 Paris, France.|Mines Paris-Tech, F-75272 Paris, France.|CNRS UMR144, 75005 Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Hupé
authors.affiliation: Division of Biophysics, Department of Biology, University of Osnabrück, 49074 Osnabrück, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Wilmes
authors.affiliation: Division of Biophysics, Department of Biology, University of Osnabrück, 49074 Osnabrück, Germany.
authors.forename: Jacob
authors.initials: J
authors.lastname: Piehler
authors.affiliation: Proteomics and Mass Spectrometry Laboratory, Institut Curie-Centre de Recherche, PSL Research University, F-75248 Paris, France.
authors.forename: Damarys
authors.initials: D
authors.lastname: Loew
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1143, 75005 Paris, France.|Centre National de la Recherche Scientifique (CNRS), UMR 3666, 75005 Paris, France.|Endocytic Trafficking and Intracellular Delivery Laboratory, Institut Curie-Centre de Recherche, PSL Research University, F-75248 Paris, France.
authors.forename: Ludger
authors.initials: L
authors.lastname: Johannes
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Gideon
authors.initials: G
authors.lastname: Schreiber
authors.affiliation: Membrane Dynamics and Mechanics of Intracellular Signaling Laboratory, Institut Curie-Centre de Recherche, PSL Research University, 26 rue d'Ulm, F-75248 Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM) U1143, 75005 Paris, France.|Centre National de la Recherche Scientifique (CNRS), UMR 3666, 75005 Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Lamaze
mesh_terms: D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D016899:Interferon-beta / Q000494:pharmacology*; D053612:Janus Kinases / Q000378:metabolism*; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects*; D033921:Vesicular Transport Proteins / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: D016898:Interferon-alpha; D046912:Multiprotein Complexes; D021122:Protein Subunits; D050791:STAT Transcription Factors; C419573:VPS35 protein, human; D033921:Vesicular Transport Proteins; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D053612:Janus Kinases; D020691:rab GTP-Binding Proteins