Altered editing in RNA editing adenosine deaminase ADAR2 gene transcripts of systemic lupus erythematosus T lymphocytes

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Abstract
Adenosine Deaminases that act on RNA (ADARs) edit gene transcripts through site-specific conversion of adenosine to inosine by hydrolytic deamination at C6 of the adenosine. ADAR2 gene transcripts are substrates for the ADAR1 and ADAR2 enzymes and their expression is regulated by editing at the - 1 and - 2 sites. Our previous experiments demonstrated up-regulation of type I interferon (IFN) inducible 150 kDa ADAR1 in systemic lupus erythematosus (SLE) T cells. In this study we investigate the role of ADAR1 and ADAR2 in editing of ADAR2 gene transcripts of healthy controls and SLE patients. The ADAR2 gene transcripts were cloned into pCR2.1-TOPO vectors. A total of 150 clones from SLE and 150 clones from controls were sequenced. Sequence analysis demonstrated A to I editing at - 1, + 10, + 23 and + 24 in normal T cells. In SLE clones site-selective editing of the - 2 site was observed as a result of type I IFN-inducible 150 kDa ADAR1 expression. These results are confirmed by analysing ADAR2 transcripts of normal T cells activated with type I IFN-alpha. Editing of the + 23 and + 24 sites was decreased in SLE T cells compared to normal controls. In addition to A to G changes, U to C discrepancies were observed in normal and SLE T cells. In SLE cells, positions - 6 and + 30 were frequently edited from U to C compared to normal controls. Taken together, these results demonstrate altered and site-selective editing in ADAR2 transcripts of SLE patients. Based on these results, it is proposed that altered transcript editing contributes to the modulation of gene expression and immune functions in SLE patients.