Tristetraprolin/ZFP36 regulates the turnover of autoimmune-associated HLA-DQ mRNAs

Abstract

We have previously demonstrated that the expression of HLA class II genes is regulated by the binding of a ribonucleoprotein complex that affects the mRNA processing. We identified protein components of a complex binding transcripts encoding the HLA-DR molecule. Here we investigate whether the same RNA binding proteins interact with 3UTR of mRNAs encoding the HLA-DQ isotype. Specifically, we focused on the HLA-DQ2.5 molecule, expressed on the surface of antigen presenting cells, and representing the main susceptibility factor for celiac disease (CD). This molecule, encoded by HLA-DQA1*05 and HLA-DQB1*02 alleles, presents the antigenic gluten peptides to CD4+ T lymphocytes, activating the autoimmune response.\n\nHere, we identified an additional component of the RNP complex, Tristetraprolin (TTP) or ZFP36, a zinc-finger protein, widely described as a factor modulating mRNA stability. TTP shows high affinity binding to 3UTR of CD-associated HLA-DQA1*05 and HLA-DQB1*02 alleles, in contrast to lower affinity binding to HLA-DQA1*01 and HLA-DQB1*05 non-CD associated alleles. Our in silico analysis, confirmed by molecular experiments, demonstrates that TTP specifically modulates the stability of the transcripts associated with celiac disease.