Hrd1-mediated BLIMP-1 ubiquitination promotes dendritic cell MHCII expression for CD4 T cell priming during inflammation

J Exp Med. 2014 Nov 17;211(12):2467-79. doi: 10.1084/jem.20140283. Epub 2014 Nov 3.

Abstract

The ubiquitin pathway plays critical roles in antigen presentation. However, the ubiquitin ligases that regulate MHC gene transcription remain unidentified. We showed that the ubiquitin ligase Hrd1, expression of which is induced by Toll-like receptor (TLR) stimulation, is required for MHC-II but not MHC-I transcription in dendritic cells (DCs). Targeted Hrd1 gene deletion in DCs diminished MHC-II expression. As a consequence, Hrd1-null DCs failed to prime CD4(+) T cells without affecting the activation of CD8(+) T cells. Hrd1 catalyzed ubiquitination and degradation of the transcriptional suppressor B lymphocyte-induced maturation protein 1 (BLIMP1) to promote MHC-II expression. Genetic suppression of Hrd1 function in DCs protected mice from myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). We identified Hrd1-mediated BLIMP1 ubiquitination as a previously unknown mechanism in programming DC for CD4(+) T cell activation during inflammation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adoptive Transfer / methods
  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Line
  • Cells, Cultured
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Gene Expression / immunology
  • HEK293 Cells
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / immunology*
  • Histocompatibility Antigens Class II / metabolism
  • Humans
  • Immunoblotting
  • Inflammation / genetics
  • Inflammation / immunology*
  • Inflammation / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Myelin-Oligodendrocyte Glycoprotein / immunology
  • Positive Regulatory Domain I-Binding Factor 1
  • Protein Binding / immunology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / genetics
  • Transcription Factors / immunology*
  • Transcription Factors / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / immunology*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination / immunology

Substances

  • Histocompatibility Antigens Class II
  • Myelin-Oligodendrocyte Glycoprotein
  • Prdm1 protein, mouse
  • Transcription Factors
  • Positive Regulatory Domain I-Binding Factor 1
  • Syvn1 protein, mouse
  • Ubiquitin-Protein Ligases