Aire's partners in the molecular control of immunological tolerance.
Aire induces the expression of a battery of peripheral-tissue self-antigens (PTAs) in thymic stromal cells, promoting the clonal deletion of differentiating T cells that recognize them. Just how Aire targets and induces PTA transcripts remains largely undefined. Screening via Aire-targeted coimmunoprecipitation followed by mass spectrometry, and validating by multiple RNAi-mediated knockdown approaches, we identified a large set of proteins that associate with Aire. They fall into four major functional classes: nuclear transport, chromatin binding/structure, transcription and pre-mRNA processing. One set of Aire interactions centered on DNA protein kinase and a group of proteins it partners with to resolve DNA double-stranded breaks or promote transcriptional elongation. Another set of interactions was focused on the pre-mRNA splicing and maturation machinery, potentially explaining the markedly more effective processing of PTA transcripts in the presence of Aire. These findings suggest a model to explain Aire's widespread targeting and induction of weakly transcribed chromatin regions.
Pubmed ID: 20085707 RIS Download
Animals | Antigens, Neoplasm | Autoantigens | Cell Line | DNA Breaks, Double-Stranded | DNA Topoisomerases, Type II | DNA-Activated Protein Kinase | DNA-Binding Proteins | Gene Expression Regulation | Humans | Immune Tolerance | Immunoprecipitation | Mass Spectrometry | Mice | Mice, SCID | Nuclear Proteins | Protein Binding | RNA Processing, Post-Transcriptional | RNA, Messenger | Thymus Gland | Transcription Factors