title: The translocon protein Sec61 mediates antigen transport from endosomes in the cytosol for cross-presentation to CD8(+) T cells.
abstract: The molecular mechanisms regulating antigen translocation into the cytosol for cross-presentation are under controversial debate, mainly because direct data is lacking. Here, we have provided direct evidence that the activity of the endoplasmic reticulum (ER) translocon protein Sec61 is essential for endosome-to-cytosol translocation. We generated a Sec61-specific intrabody, a crucial tool that trapped Sec61 in the ER and prevented its recruitment into endosomes without influencing Sec61 activity and antigen presentation in the ER. Expression of this ER intrabody inhibited antigen translocation and cross-presentation, demonstrating that endosomal Sec61 indeed mediates antigen transport across endosomal membranes. Moreover, we showed that the recruitment of Sec61 toward endosomes, and hence antigen translocation and cross-presentation, is dependent on dendritic cell activation by Toll-like receptor (TLR) ligands. These data shed light on a long-lasting question regarding antigen cross-presentation and point out a role of the ER-associated degradation machinery in compartments distinct from the ER.
authors.affiliation: Life and Medical Sciences (LIMES) Institute, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Zehner
authors.affiliation: Institute of Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, Langer Kamp 19b, 38106 Braunschweig, Germany.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Marschall
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center (LUMC), Albinusdreef 2, 2333ZA Leiden, the Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Bos
authors.affiliation: Life and Medical Sciences (LIMES) Institute, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany.
authors.forename: Jan-Gero
authors.initials: JG
authors.lastname: Schloetel
authors.affiliation: Life and Medical Sciences (LIMES) Institute, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kreer
authors.affiliation: Life and Medical Sciences (LIMES) Institute, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Fehrenschild
authors.affiliation: Department of Orthopedics and Trauma Surgery, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Limmer
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Albinusdreef 2, 2333ZA Leiden, the Netherlands.
authors.forename: Ferry
authors.initials: F
authors.lastname: Ossendorp
authors.affiliation: Life and Medical Sciences (LIMES) Institute, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lang
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center (LUMC), Albinusdreef 2, 2333ZA Leiden, the Netherlands.
authors.forename: Abraham J
authors.initials: AJ
authors.lastname: Koster
authors.affiliation: Institute of Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, Langer Kamp 19b, 38106 Braunschweig, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Dübel
authors.affiliation: Life and Medical Sciences (LIMES) Institute, University of Bonn, Carl-Troll-Str. 31, 53115 Bonn, Germany. Electronic address: burgdorf@uni-bonn.de.
authors.forename: Sven
authors.initials: S
authors.lastname: Burgdorf
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes; D002460:Cell Line; D045142:Cross-Priming / Q000276:immunology*; D003600:Cytosol / Q000276:immunology / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D021381:Protein Transport; D000069816:SEC Translocation Channels
chemical_list: D000941:Antigens; D008565:Membrane Proteins; D000069816:SEC Translocation Channels