title: A novel internalization motif regulates human IFN-γ R1 endocytosis.
abstract: This study tested the hypothesis that the IFN-γ R1 287-YVSLI-91 intracellular motif regulates its endocytosis. IFN-γ exerts its biological activities by interacting with a specific cell-surface RC composed of two IFN-γ R1 and two IFN-γ R2 chains. Following IFN-γ binding and along with the initiation of signal transduction, the ligand and IFN-γ R1 are internalized. Two major types of consensus-sorting signals are described in receptors, which are rapidly internalized from the plasma membrane to intracellular compartments: tyrosine-based and dileucine-based internalization motifs. Transfection of HEK 293 cells and IFN-γ R1-deficient fibroblasts with WT and site-directed, mutagenesis-generated mutant IFN-γ R1 expression vectors helped us to identify region IFN-γ R1 287-YVSLI-291 as the critical domain required for IFN-γ-induced IFN-γ R1 internalization and Y287 and LI290-291 as part of a common structure essential for receptor endocytosis and function. This new endocytosis motif, YxxLI, shares characteristics of tyrosine-based and dileucine-based internalization motifs and is highly conserved in IFN-γ Rs across species. The IFN-γ R1 270-LI-271 dileucine motif, previously thought to be involved in this receptor endocytosis, showed to be unnecessary for receptor endocytosis.
authors.affiliation: Servicio de Inmunología y Reumatología, Hospital Nacional de Pediatría J. P. Garrahan, Buenos Aires, Argentina.
authors.forename: Judith
authors.initials: J
authors.lastname: Yancoski
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Sadat
authors.forename: Nadia
authors.initials: N
authors.lastname: Aksentijevich
authors.forename: Andrea
authors.initials: A
authors.lastname: Bernasconi
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.forename: Sergio D
authors.initials: SD
authors.lastname: Rosenzweig
mesh_terms: D020816:Amino Acid Motifs / Q000276:immunology; D000595:Amino Acid Sequence; D017124:Conserved Sequence / Q000276:immunology; D004705:Endocytosis / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007930:Leucine / Q000737:chemistry* / Q000378:metabolism*; D008969:Molecular Sequence Data; D021382:Protein Sorting Signals / Q000502:physiology; D017471:Receptors, Interferon / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism; D000096743:Interferon gamma Receptor
chemical_list: D007930:Leucine; D021382:Protein Sorting Signals; D017471:Receptors, Interferon; D014443:Tyrosine; D000096743:Interferon gamma Receptor