A role for the endoplasmic reticulum protein retrotranslocation machinery during crosspresentation by dendritic cells.
Crosspresentation of exogenous antigens (Ags) to CD8(+) T cells by dendritic cells generally requires their entry into the cytosol. Here we show that both soluble and phagocytosed extracellular Ags accessed the cytosol via molecular components required for endoplasmic reticulum (ER)-associated degradation (ERAD). Exogenous Pseudomonas aeruginosa Exotoxin A, which inhibits protein translocation from the ER to the cytosol, abrogated crosspresentation. Exotoxin A also prevented the transporter associated with antigen processing (TAP) inhibitor, ICP47, from entering the cytosol and blocking TAP-mediated peptide transport. In an in vitro model of retrotranslocation, the AAA ATPase p97, an enzyme critical for ERAD, was the only cytosolic cofactor required for protein export from isolated phagosomes. Functional p97 was also required for crosspresentation but not conventional presentation. Thus, crosspresentation appears to result from an adaptation of the retrotranslocation mechanisms involved in the degradation of misfolded ER proteins.
Ackerman
Anne L
AL
Howard Hughes Medical Institute, Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Giodini
Alessandra
A
Cresswell
Peter
P
D036002:ADP Ribose Transferases / Q000494:pharmacology; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D017951:Antigen Presentation / Q000187:drug effects; D000941:Antigens / Q000378:metabolism*; D001427:Bacterial Toxins / Q000494:pharmacology; D002478:Cells, Cultured; D045142:Cross-Priming / Q000187:drug effects; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005098:Exotoxins / Q000494:pharmacology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000494:pharmacology; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D010588:Phagosomes / Q000276:immunology*; D017510:Protein Folding; D021381:Protein Transport / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D014764:Viral Proteins / Q000235:genetics / Q000494:pharmacology; D037521:Virulence Factors / Q000494:pharmacology; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D018528:ATP-Binding Cassette Transporters; D000251:Adenosine Triphosphatases; D000941:Antigens; D001427:Bacterial Toxins; D005098:Exotoxins; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D011506:Proteins; D011994:Recombinant Proteins; D014764:Viral Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C105843:ICP47 protein, Herpes simplex virus; C477327:transporter associated with antigen processing (TAP); C404942:p97 ATPase