{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T20:50:07Z","timestamp":1784580607944,"version":"3.55.0"},"reference-count":24,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,12,4]],"date-time":"2019-12-04T00:00:00Z","timestamp":1575417600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CNR-DSB","award":["Progetto Bandiera \u201cInterOmics\u201d 2017"],"award-info":[{"award-number":["Progetto Bandiera \u201cInterOmics\u201d 2017"]}]},{"DOI":"10.13039\/501100003852","name":"Regione Campania","doi-asserted-by":"publisher","award":["PO FESR 2014-2020 \u201cSATIN\u201d"],"award-info":[{"award-number":["PO FESR 2014-2020 \u201cSATIN\u201d"]}],"id":[{"id":"10.13039\/501100003852","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Cambridge.","award":["Project from Centre for Trophoblast Research"],"award-info":[{"award-number":["Project from Centre for Trophoblast Research"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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\u2032UTR 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\u2032UTR 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\u2032UTR, conferring a rapid turnover, in contrast to lower affinity binding to HLA non-CD associated mRNA.<\/jats:p>","DOI":"10.3390\/cells8121570","type":"journal-article","created":{"date-parts":[[2019,12,5]],"date-time":"2019-12-05T03:16:36Z","timestamp":1575515796000},"page":"1570","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Tristetraprolin\/ZFP36 Regulates the Turnover of Autoimmune-Associated HLA-DQ mRNAs"],"prefix":"10.3390","volume":"8","author":[{"given":"Laura","family":"Pisapia","sequence":"first","affiliation":[{"name":"Institute of Genetics and Biophysics \u201cAdriano Buzzati Traverso\u201d CNR, Via Pietro Castellino, 111, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0598-3793","authenticated-orcid":false,"given":"Russell S.","family":"Hamilton","sequence":"additional","affiliation":[{"name":"Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Site, Cambridge CB2 3DY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Farina","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u201cAdriano Buzzati Traverso\u201d CNR, Via Pietro Castellino, 111, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vito","family":"D\u2019Agostino","sequence":"additional","affiliation":[{"name":"Centre for Cellular, Computational and Integrative Biology-CIBIO, University of Trento, via Sommarive 9, 38123 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"Barba","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u201cAdriano Buzzati Traverso\u201d CNR, Via Pietro Castellino, 111, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7257-4754","authenticated-orcid":false,"given":"Maria","family":"Strazzullo","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u201cAdriano Buzzati Traverso\u201d CNR, Via Pietro Castellino, 111, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1652-3415","authenticated-orcid":false,"given":"Alessandro","family":"Provenzani","sequence":"additional","affiliation":[{"name":"Centre for Cellular, Computational and Integrative Biology-CIBIO, University of Trento, via Sommarive 9, 38123 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Gianfrani","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Cell Biology-CNR, Via Pietro Castellino, 111, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8937-9018","authenticated-orcid":false,"given":"Giovanna","family":"Del Pozzo","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u201cAdriano Buzzati Traverso\u201d CNR, Via Pietro Castellino, 111, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S21","DOI":"10.1016\/S0092-8674(02)00696-7","article-title":"Genetic control of MHC class II expression","volume":"109","author":"Ting","year":"2002","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1038\/nri1708","article-title":"Regulation of MHC class II gene expression by the class II transactivator","volume":"5","author":"Reith","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7263","DOI":"10.1093\/nar\/gkr278","article-title":"EBP1 and DRBP76\/NF90 binding proteins are included in the major histocompatibility complex class II RNA operon","volume":"39","author":"Corso","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3772","DOI":"10.1093\/nar\/gkt059","article-title":"Co-regulated expression of alpha and beta mRNAs encoding HLA-DR surface heterodimers is mediated by the MHCII RNA operon","volume":"41","author":"Pisapia","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1002\/ijc.30165","article-title":"Opposing roles of the two isoforms of ErbB3 binding protein 1 in human cancer cells","volume":"139","author":"Ko","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17111","DOI":"10.3390\/ijms140817111","article-title":"NF90 in posttranscriptional gene regulation and microRNA biogenesis","volume":"14","author":"Masuda","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1146\/annurev-immunol-040210-092915","article-title":"Integration of genetic and immunological insights into a model of celiac disease pathogenesis","volume":"29","author":"Abadie","year":"2011","journal-title":"Annu. Rev. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.jaut.2015.07.014","article-title":"Immunogenetics of type 1 diabetes: A comprehensive review","volume":"64","author":"Noble","year":"2015","journal-title":"J. Autoimmun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jaut.2016.03.016","article-title":"HLA-DQ2.5 genes associated to celiac disease risk are preferentially expressed respect to non-predisposing HLA genes: Implication for anti-gluten T cell response","volume":"70","author":"Pisapia","year":"2016","journal-title":"J. Autoimmun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1016\/j.bbagrm.2013.02.003","article-title":"Tristetraprolin (TTP): Interactions with mRNA and proteins, and current thoughts on mechanisms of action","volume":"1829","author":"Brooks","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"R12","DOI":"10.1186\/gb-2014-15-1-r12","article-title":"Global target mRNA specification and regulation by the RNA-binding protein ZFP36","volume":"15","author":"Mukherjee","year":"2014","journal-title":"Genome Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1073\/pnas.1519906113","article-title":"Enhanced stability of tristetraprolin mRNA protects mice against immune-mediated inflammatory pathologies","volume":"113","author":"Patial","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"868","DOI":"10.15252\/msb.20156628","article-title":"Tristetraprolin binding site atlas in the macrophage transcriptome reveals a switch for inflammation resolution","volume":"12","author":"Sedlyarov","year":"2016","journal-title":"Mol. Syst. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Bhandare, S., Goldberg, D.S., and Dowell, R. (2017). Discriminating between HuR and TTP binding sites using the k-spectrum kernel method. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0175988"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"W135","DOI":"10.1093\/nar\/gkh449","article-title":"Sfold web server for statistical folding and rational design of nucleic acids","volume":"32","author":"Ding","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1093\/bioinformatics\/btv748","article-title":"Foldalign 2.5: Multithreaded implementation for pairwise structural RNA alignment","volume":"32","author":"Sundfeld","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jaut.2017.12.016","article-title":"Expression level of risk genes of MHC class II is a susceptibility factor for autoimmunity: New insights","volume":"89","author":"Gianfrani","year":"2018","journal-title":"J. Autoimmun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/j.tips.2016.07.002","article-title":"Tristetraprolin as a Therapeutic Target in Inflammatory Disease","volume":"37","author":"Patial","year":"2016","journal-title":"Trends Pharm. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"D\u2019Agostino, V.G., Adami, V., and Provenzani, A. (2013). A novel high throughput biochemical assay to evaluate the HuR protein-RNA complex formation. PLoS ONE., 8.","DOI":"10.1371\/journal.pone.0072426"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/0022-2836(70)90057-4","article-title":"A general method applicable to the search for similarities in the amino acid sequence of two proteins","volume":"48","author":"Needleman","year":"1970","journal-title":"J. Mol. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/1748-7188-6-26","article-title":"ViennaRNA Package 2.0","volume":"6","author":"Lorenz","year":"2011","journal-title":"Algorithms Mol. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1896","DOI":"10.1371\/journal.pcbi.0030193","article-title":"Fast pairwise structural RNA alignments by pruning of the dynamical programming matrix","volume":"3","author":"Havgaard","year":"2007","journal-title":"PLoS Comput. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3377","DOI":"10.1093\/bioinformatics\/btv372","article-title":"Forna (force-directed RNA): Simple and effective online RNA secondary structure diagrams","volume":"31","author":"Kerpedjiev","year":"2015","journal-title":"Bioinformatics"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/12\/1570\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:40:13Z","timestamp":1760190013000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/12\/1570"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,4]]},"references-count":24,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["cells8121570"],"URL":"https:\/\/doi.org\/10.3390\/cells8121570","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/337907","asserted-by":"object"}]},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,4]]}}}