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Open AccessArticle

Tristetraprolin/ZFP36 Regulates the Turnover of Autoimmune-Associated HLA-DQ mRNAs

1
Institute of Genetics and Biophysics “Adriano Buzzati Traverso” CNR, Via Pietro Castellino, 111, 80131 Naples, Italy
2
Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Site, Cambridge CB2 3DY, UK
3
Centre for Cellular, Computational and Integrative Biology-CIBIO, University of Trento, via Sommarive 9, 38123 Trento, Italy
4
Institute of Biochemistry and Cell Biology-CNR, Via Pietro Castellino, 111, 80131 Naples, Italy
*
Author to whom correspondence should be addressed.
Co-first authors.
Cells 2019, 8(12), 1570; https://doi.org/10.3390/cells8121570
Received: 24 October 2019 / Revised: 27 November 2019 / Accepted: 28 November 2019 / Published: 4 December 2019
(This article belongs to the Special Issue Bioinformatics and Computational Biology 2019)
HLA class II genes encode highly polymorphic heterodimeric proteins functioning to present antigens to T cells and stimulate a specific immune response. Many HLA genes are strongly associated with autoimmune diseases as they stimulate self-antigen specific CD4+ T cells driving pathogenic responses against host tissues or organs. High expression of HLA class II risk genes is associated with autoimmune diseases, influencing the strength of the CD4+ T-mediated autoimmune response. The expression of HLA class II genes is regulated at both transcriptional and post-transcriptional levels. Protein components of the RNP complex binding the 3′UTR and affecting mRNA processing have previously been identified. Following on from this, the regulation of HLA-DQ2.5 risk genes, the main susceptibility genetic factor for celiac disease (CD), was investigated. The DQ2.5 molecule, encoded by HLA-DQA1*05 and HLA-DQB1*02 alleles, presents the antigenic gluten peptides to CD4+ T lymphocytes, activating the autoimmune response. The zinc-finger protein Tristetraprolin (TTP) or ZFP36 was identified to be a component of the RNP complex and has been described as a factor modulating mRNA stability. The 3′UTR of CD-associated HLA-DQA1*05 and HLA-DQB1*02 mRNAs do not contain canonical TTP binding consensus sequences, therefore an in silico approach focusing on mRNA secondary structure accessibility and stability was undertaken. Key structural differences specific to the CD-associated mRNAs were uncovered, allowing them to strongly interact with TTP through their 3′UTR, conferring a rapid turnover, in contrast to lower affinity binding to HLA non-CD associated mRNA. View Full-Text
Keywords: celiac disease; Human Leukocyte Antigen (HLA); RNA binding protein; RNA stability; RNA structure celiac disease; Human Leukocyte Antigen (HLA); RNA binding protein; RNA stability; RNA structure
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Pisapia, L.; Hamilton, R.S.; Farina, F.; D’Agostino, V.; Barba, P.; Strazzullo, M.; Provenzani, A.; Gianfrani, C.; Del Pozzo, G. Tristetraprolin/ZFP36 Regulates the Turnover of Autoimmune-Associated HLA-DQ mRNAs. Cells 2019, 8, 1570.

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