title: The Hsc/Hsp70 co-chaperone network controls antigen aggregation and presentation during maturation of professional antigen presenting cells.
abstract: The maturation of mouse macrophages and dendritic cells involves the transient deposition of ubiquitylated proteins in the form of dendritic cell aggresome-like induced structures (DALIS). Transient DALIS formation was used here as a paradigm to study how mammalian cells influence the formation and disassembly of protein aggregates through alterations of their proteostasis machinery. Co-chaperones that modulate the interplay of Hsc70 and Hsp70 with the ubiquitin-proteasome system (UPS) and the autophagosome-lysosome pathway emerged as key regulators of this process. The chaperone-associated ubiquitin ligase CHIP and the ubiquitin-domain protein BAG-1 are essential for DALIS formation in mouse macrophages and bone-marrow derived dendritic cells (BMDCs). CHIP also cooperates with BAG-3 and the autophagic ubiquitin adaptor p62 in the clearance of DALIS through chaperone-assisted selective autophagy (CASA). On the other hand, the co-chaperone HspBP1 inhibits the activity of CHIP and thereby attenuates antigen sequestration. Through a modulation of DALIS formation CHIP, BAG-1 and HspBP1 alter MHC class I mediated antigen presentation in mouse BMDCs. Our data show that the Hsc/Hsp70 co-chaperone network controls transient protein aggregation during maturation of professional antigen presenting cells and in this way regulates the immune response. Similar mechanisms may modulate the formation of aggresomes and aggresome-like induced structures (ALIS) in other mammalian cell types.
authors.affiliation: Institute for Cell Biology, Rheinische Friedrich-Wilhelms-University Bonn, Bonn, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Kettern
authors.forename: Christian
authors.initials: C
authors.lastname: Rogon
authors.forename: Andreas
authors.initials: A
authors.lastname: Limmer
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Schild
authors.forename: Jörg
authors.initials: J
authors.lastname: Höhfeld
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000166:cytology* / Q000276:immunology; D000941:Antigens / Q000378:metabolism*; D001343:Autophagy / Q000276:immunology; D002454:Cell Differentiation; D050883:HSC70 Heat-Shock Proteins / Q000276:immunology*; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology*; D007109:Immunity; D051379:Mice; D055503:Protein Multimerization
chemical_list: D000941:Antigens; D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins