Aire's partners in the molecular control of immunological tolerance

Cell. 2010 Jan 8;140(1):123-35. doi: 10.1016/j.cell.2009.12.030.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / metabolism
  • Autoantigens / genetics*
  • Autoantigens / immunology
  • Cell Line
  • DNA Breaks, Double-Stranded
  • DNA Topoisomerases, Type II / metabolism
  • DNA-Activated Protein Kinase / metabolism
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation*
  • Humans
  • Immune Tolerance*
  • Immunoprecipitation
  • Mass Spectrometry
  • Mice
  • Mice, SCID
  • Nuclear Proteins / metabolism
  • Protein Binding
  • RNA Processing, Post-Transcriptional
  • RNA, Messenger / metabolism
  • Thymus Gland / cytology
  • Thymus Gland / immunology*
  • Transcription Factors / metabolism*

Substances

  • APECED protein
  • Antigens, Neoplasm
  • Autoantigens
  • DNA-Binding Proteins
  • Nuclear Proteins
  • RNA, Messenger
  • Transcription Factors
  • DNA-Activated Protein Kinase
  • Prkdc protein, mouse
  • DNA Topoisomerases, Type II