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.
Mesh Terms:
Animals, Antigens, Neoplasm, Autoantigens, Cell Line, DNA Breaks, Double-Stranded, DNA Topoisomerases, Type II, Eukaryotic, 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
Cell
Date: Jan. 08, 2010
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