Sequential Modifications in Class II Transactivator Isoform 1 Induced by Lipopolysaccharide Stimulate Major Histocompatibility Complex Class II Transcription in Macrophages

Tadashi Nishiya,B. Matija Peterlin,Gorazd Drozina,Jiri Kohoutek

doi:10.1074/jbc.m608538200

Tadashi Nishiya, B. Matija Peterlin + Show 2 more

Open Access

https://doi.org/10.1074/jbc.m608538200

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Abstract

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.

Highlights

Macrophages are antigen-presenting cells that remove and digest invading pathogens as well as present antigenic peptides, directing the immune response against them
We found that in these cells, lipopolysaccharide stimulates the expression of major histocompatibility complex class (MHC) II genes via the activation of extracellular regulated kinase 1/2 (Erk1/2), which is mediated by Toll-like receptor 4
Modifications of Class II Transactivator transcription elongation factor b (P-TEFb), which is composed of cyclin T1 (CycT1) and cyclin-dependent kinase 9 (Cdk9), the monoubiquitylated VP16 protein increases the rates of elongation rather than initiation of transcription [23]

Summary

Introduction

Macrophages are antigen-presenting cells that remove and digest invading pathogens as well as present antigenic peptides, directing the immune response against them. These results indicate that LPS activates Erk1/2 and increases the expression of MHC II determinants in primary macrophages via TLR4. LPS induced the expression of MHC II genes in RAW 264.7 cells equivalently to primary macrophages (Fig. 1B, top panel, compare lanes 1 and 2).

Results

Conclusion