Maturation of human dendritic cells is accompanied by functional remodelling of the ubiquitin-proteasome system.
Dendritic cell maturation is the process by which immature dendritic cells differentiate into fully competent antigen-presenting cells that initiate T cell responses. Although some mechanistic aspects of DC maturation have begun to be characterised, very little is known about the genetic events regulating the ubiquitin-proteasome system which plays a key role at various levels of the immune response. Therefore, we here investigated the expression of more than 1000 genes related to the ubiquitin-proteasome system in maturing dendritic cells following various stimuli and identified a specific set of transcripts induced by lipopolysaccharide and/or Poly(I:C) which is largely distinct from that induced by CD40 ligand or pro-inflammatory cytokines. This group of genes was dependent on a type I interferon autocrine loop and included E1 and E2 enzymes, E3-ligases, de-ubiquitylating enzymes, proteasome components as well as the ubiquitin-like modifiers ISG15 and FAT10. We further demonstrate that the increased expression of the E2 enzyme UBE2L6 (UbcH8) is required for efficient antigen cross-presentation by dendritic cells. In summary, our data underline the importance of remodelling the ubiquitin-proteasome system for dendritic cell function.
Ebstein
Frédéric
F
Charité-Universitätsmedizin Berlin, CCM, Institut für Biochemie, Monbijoustr. 2, D-10117 Berlin, Germany.
Lange
Nicole
N
Urban
Sabrina
S
Seifert
Ulrike
U
Krüger
Elke
E
Kloetzel
Peter-Michael
PM
D017951:Antigen Presentation / Q000276:immunology; D023201:CD40 Ligand / Q000494:pharmacology; D045142:Cross-Priming / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D011070:Poly I-C / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D014452:Ubiquitins / Q000276:immunology / Q000378:metabolism
D016207:Cytokines; D008070:Lipopolysaccharides; C109184:UBD protein, human; D025801:Ubiquitin; D014452:Ubiquitins; D023201:CD40 Ligand; C471622:UBE2L6 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D046988:Proteasome Endopeptidase Complex; D011070:Poly I-C