Tuesday, October 10, 2006

Autoimmunity and Ubiquitin ligases

drj writes "Mutations in the AIRE (autoimmune regulator) gene cause ‘autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy’ (APECED, OMIM 240300), a rare autoimmune disease marked by lymphocyte infiltration and antibody deposition in multiple organs (review). Known human AIRE mutant alleles are recessive and were identified by positional cloning at 21q22.3 in 1997. Mice deficient in AIRE also develop autoimmune disease. AIRE protein is mostly nuclear and can activate transcription when linked to a DNA binding domain. AIRE increases the ectopic (out of place) expression of a ‘substantial’ number of genes in the thymus, which may promote T cell tolerance (self shadow). Failure to encounter these proteins in the thymus may permit autoimmune T cells to survive and mature, leading to autoimmunity. Here, disease-causing mutations in AIRE are shown to abolish ubiquitin (Ub) ligase activity without reducing transcription activation, strongly suggesting that Ub ligation is AIRE’s primary activity. The Cbl family of Ub ligases are known to deactivate the T cell receptor by targeting the associated tyrosine kinases. Is it too simplistic to ask which is (are) AIRE’s mechanism(s)?
PubMed Uchida et al., J. Exp. Med. 199(2) 167-172, 2004"
AIRE Functions As an E3 Ubiquitin Ligase. Daisuke Uchida, Shigetsugu Hatakeyama, Akemi Matsushima, Hongwei Han, Satoshi Ishido, Hak Hotta, Jun Kudoh, Nobuyoshi Shimizu, Vassilis Doucas, Keiichi I. Nakayama, Noriyuki Kuroda, and Mitsuru Matsumoto J. Exp. Med. Volume 199, Number 2, January 19, 2004 167–172


Anonymous said...

The Anderson paper demonstrates a strong regulation by AIRE of ectopic gene expression in the thymus, most clearly insulin by quantitative PCR. However, AIRE deficient mice are apparently not diabetic (corrections welcome) and less than 20% of humans with AIRE mutations are diabetic (the cited review). Thus, the link between ectopic expression in the thymus and disease is not very strong.

Anonymous said...

This recent JEM paper by Derbinski et al. [nih.gov] shows that some regions of the genome are transcriptionally active in thymic epithelial cells. These regions include AIRE-dependent and -independent genes (promoters).