Aire's Partners in the Molecular Control of Immunological Tolerance

SummaryAire 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.PaperClip To listen to this audio, enable JavaScript on your browser. However, you can download and play the audio by clicking on the icon belowHelp with MP3 filesOptionsDownload audio (2810 K)

Graphical SummaryFigure optionsDownload high-quality image (317 K)Download as PowerPoint slideHighlights
► To promote immune tolerance, Aire induces ectopic expression of genes in the thymus
► Aire partners with numerous factors to regulate gene expression at multiple levels
► With DNA-PK and Topoisomerase 2 Aire enhances formation of DNA double-stranded breaks
► Aire also regulates gene expression at the level of pre-mRNA processing