Sequential modifications in class II transactivator isoform 1 induced by lipopolysaccharide stimulate major histocompatibility complex class II transcription in macrophages.
By presenting antigenic peptides on major histocompatibility complex class (MHC) II determinants to CD4(+) T cells, macrophages help to direct the establishment of adaptive immunity. We found that in these cells, lipopolysaccharide stimulates the expression of MHC II genes via the activation of Erk1/2, which is mediated by Toll-like receptor 4. Erk1/2 then phosphorylates the serine at position 357, which is located in a degron of CIITA isoform 1 that leads to its monoubiquitylation. Thus modified, CIITA isoform 1 binds P-TEFb, which mediates the elongation of RNA polymerase II and co-transcriptional processing of nascent transcripts. This induction leads to the expression of MHC II genes. Subsequent polyubiquitylation results in the degradation of CIITA isoform 1. Thus, the signaling cascade from Toll-like receptor 4 to CIITA isoform 1 represents one connection between innate and adaptive immunity in macrophages.
Drozina
Gorazd
G
Department of Medicine, Rosalind Russell Medical Research Center, University of California San Francisco, San Francisco, California 94143, USA.
Kohoutek
Jiri
J
Nishiya
Tadashi
T
Peterlin
B Matija
BM
D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D011817:Rabbits; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic
D000949:Histocompatibility Antigens Class II; D008070:Lipopolysaccharides; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D020033:Protein Isoforms; D051197:Toll-Like Receptor 4; D015534:Trans-Activators