Sequence variation in promoter of Ica1 gene, which encodes protein implicated in type 1 diabetes, causes transcription factor autoimmune regulator (AIRE) to increase its binding and down-regulate expression

Samantha M. Bonner, Susan L. Pietropaolo, Yong Fan, Yigang Chang, Praveen Sethupathy, Michael P. Morran, Megan Beems, Nick Giannoukakis, Giuliana Trucco, Michael O. Palumbo, Michele Solimena, Alberto Pugliese, Constantin Polychronakos, Massimo Trucco, Massimo Pietropaolo

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12 Scopus citations

Abstract

ICA69 (islet cell autoantigen 69 kDa) is a protein implicated in type 1 diabetes mellitus in both the non-obese diabetic (NOD) mouse model and humans. ICA69 is encoded by the Ica1 gene on mouse chromosome 6 A1-A2. We previously reported reduced ICA69 expression in the thymus of NOD mice compared with thymus of several non-diabetic mouse strains. We propose that reduced thymic ICA69 expression could result from variations in transcriptional regulation of the gene and that polymorphisms within the Ica1 core promoter may partially determine this transcriptional variability. We characterized the functional promoter of Ica1 in NOD mice and compared it with the corresponding portions of Ica1 in non-diabetic C57BL/6 mice. Luciferase reporter constructs demonstrated that the NOD Ica1 promoter region exhibited markedly reduced luciferase expression in transiently transfected medullary thymus epithelial (mTEC +) and B-cell (M12)-derived cell lines. However, in a non-diabetic strain, C57BL/6, the Ica1 promoter region was transcriptionally active when transiently transfected into the same cell lines. We concomitantly identified five single nucleotide polymorphisms within the NOD Ica1 promoter. One of these single nucleotide polymorphisms increases the binding affinity for the transcription factor AIRE (autoimmune regulator), which is highly expressed in thymic epithelial cells, where it is known to play a key role regulating self-antigen expression. We conclude that polymorphisms within the NOD Ica1 core promoter may determine AIRE-mediated down-regulation of ICA69 expression in medullary thymic epithelial cells, thus providing a novel mechanistic explanation for the loss of immunologic tolerance to this self-antigen in autoimmunity.

Original languageEnglish (US)
Pages (from-to)17882-17893
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number21
DOIs
StatePublished - May 18 2012

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Bonner, S. M., Pietropaolo, S. L., Fan, Y., Chang, Y., Sethupathy, P., Morran, M. P., Beems, M., Giannoukakis, N., Trucco, G., Palumbo, M. O., Solimena, M., Pugliese, A., Polychronakos, C., Trucco, M., & Pietropaolo, M. (2012). Sequence variation in promoter of Ica1 gene, which encodes protein implicated in type 1 diabetes, causes transcription factor autoimmune regulator (AIRE) to increase its binding and down-regulate expression. Journal of Biological Chemistry, 287(21), 17882-17893. https://doi.org/10.1074/jbc.M111.319020