title: Regulation of antigen transport into the cytosol for cross-presentation by ubiquitination of the mannose receptor.
abstract: The molecular mechanisms governing cross-presentation of extracellular antigens on MHC I molecules are not fully understood. It is generally assumed that, in order to be processed for cross-presentation, most antigens need to be transported from the endosomal compartment into the cytosol to be processed by the cytosolic proteasome. The mechanisms regulating such intracellular transport are largely unknown. In a recent study, we demonstrated that the ubiquitination status of the mannose receptor (MR), an endocytic receptor that targets its ligands specifically toward cross-presentation, can regulate such antigen export into the cytosol. Poly-ubiquitination of the MR recruits p97 toward the endosomal membrane, which is essential for antigen translocation out of the endosomes. Furthermore, we identified Tumor Susceptibility Gene 101 (TSG101) as an important regulator of MR poly-ubiquitination and hence of antigen translocation and cross-presentation. Additionally, we describe in this article some perspectives and open questions regarding the molecular mechanisms of cross-presentation. In particular, we highlight the search for proteins regulating antigen translocation in the cytosol, the recruitment of ER proteins and proteasomes toward antigen-containing endosomes and the importance of antigen stability for cross-presentation.
authors.affiliation: Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Zehner
authors.forename: Sven
authors.initials: S
authors.lastname: Burgdorf
mesh_terms: D017951:Antigen Presentation; D045142:Cross-Priming; D003600:Cytosol / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D011992:Endosomes / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D021381:Protein Transport; D011956:Receptors, Cell Surface / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D054875:Ubiquitination; D000099177:Tsg101 Protein
chemical_list: D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D015395:Histocompatibility Antigens Class I; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D009687:Nuclear Proteins; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D000099177:Tsg101 Protein; C094680:nuclear protein import factor p97