title: Mannose receptor polyubiquitination regulates endosomal recruitment of p97 and cytosolic antigen translocation for cross-presentation.
abstract: The molecular mechanisms regulating noncanonical protein transport across cellular membranes are poorly understood. Cross-presentation of exogenous antigens on MHC I molecules by dendritic cells (DCs) generally requires antigen translocation from the endosomal compartment into the cytosol for proteasomal degradation. In this study, we demonstrate that such translocation is controlled by the endocytic receptor and regulated by ubiquitination. Antigens internalized by the mannose receptor (MR), an endocytic receptor that targets its ligands specifically toward cross-presentation, were translocated into the cytosol only after attachment of a lysin48-linked polyubiquitin chain to the cytosolic region of the MR. Furthermore, we identify TSG101 as a central regulator of MR ubiquitination and antigen translocation. Importantly, we demonstrate that MR polyubiquitination mediates the recruitment of p97, a member of the ER-associated degradation machinery that provides the driving force for antigen translocation, toward the endosomal membrane, proving the central role of the endocytic receptor and its ubiquitination in antigen translocation.
authors.affiliation: Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Zehner
authors.forename: Achmet Imam
authors.initials: AI
authors.lastname: Chasan
authors.forename: Verena
authors.initials: V
authors.lastname: Schuette
authors.forename: Maria
authors.initials: M
authors.lastname: Embgenbroich
authors.forename: Thomas
authors.initials: T
authors.lastname: Quast
authors.forename: Waldemar
authors.initials: W
authors.lastname: Kolanus
authors.forename: Sven
authors.initials: S
authors.lastname: Burgdorf
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000941:Antigens / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D045142:Cross-Priming; D003600:Cytosol / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004705:Endocytosis / Q000276:immunology; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011992:Endosomes / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010047:Ovalbumin / Q000276:immunology / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism; D021381:Protein Transport / Q000276:immunology; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054875:Ubiquitination / Q000276:immunology; D000099177:Tsg101 Protein
chemical_list: D000251:Adenosine Triphosphatases; D000941:Antigens; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D049452:Green Fluorescent Proteins; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D009687:Nuclear Proteins; D010047:Ovalbumin; D025821:Polyubiquitin; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D000099177:Tsg101 Protein; C404942:p97 ATPase