Abstract
Regulation of major histocompatibility complex class II (MHC-II) expression is important not only to maintain a diverse pool of MHC-II-peptide complexes but also to prevent development of autoimmunity. The membrane-associated RING-CH (March) E3 ubiquitin ligase March-I regulates ubiquitination and turnover of MHC-II-peptide complexes in resting dendritic cells (DCs) and B cells. However, activation of either cell type terminates March-I expression, thereby stabilizing MHC-II-peptide complexes. Despite March-I's important role in the biology of antigen-presenting cells (APCs), how expression of March-I mRNA is regulated remains unknown. We now show that both DCs and B cells possess a distinct isoform of March-I whose expression is regulated by a promoter located within the March-I gene. Using March-I promoter fragments to drive expression of GFP, we also identified a core promoter for expression of March-I in DCs and B cells, but not in fibroblasts, kidney cells, or epithelial cells, that contains regulatory regions that down-regulate March-I expression upon activation of DCs. Curiously, we found downstream sequence elements, present in the first coding exon of March-I in APCs, that confer regulation of March-I expression in activated APCs. In summary, our study identifies regulatory regions of the March-I gene that confer APC-specific expression and activation-induced modulation of March-I expression in DCs and B cells.
Highlights
Regulation of major histocompatibility complex class II (MHC-II) expression is important to maintain a diverse pool of MHC-II–peptide complexes and to prevent development of autoimmunity
MHC-II complexes move to the antigen-presenting cells (APCs) surface where they can be surveyed by T-cell receptors (TCRs) expressed on CD4 T cells [2, 3]
Must the pMHC-II complexes on the APC surface present the appropriate pMHC-II to the TCR on an antigen-specific T cell, but sustained engagement by pMHC-II with the TCR is necessary for complete T-cell activation [5]
Summary
A major isoform of the E3 ubiquitin ligase March-I in antigenpresenting cells has regulatory sequences within its gene. The membrane-associated RING-CH (March) E3 ubiquitin ligase March-I regulates ubiquitination and turnover of MHC-II–peptide complexes in resting dendritic cells (DCs) and B cells. APCs, including dendritic cells (DCs) and B cells, internalize potential antigens and degrade them into peptide fragments that bind to MHC-II molecules in endo/lysosomal compartments [1]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We have examined the March-I gene, identified the March-I isoform present in APCs, and identified the regulatory sequences within the March-I gene that confer tissue-specific expression and activation-induced repression of March-I transcription in DCs
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