The lncRNA LUCAT1 is elevated in inflammatory disease and restrains inflammation by regulating the splicing and stability of NR4A2
| Autor: | Tim Vierbuchen, Shiuli Agarwal, John L. Johnson, Liraz Galia, Xuqiu Lei, Karina Stein, David Olagnier, Karoline I. Gaede, Christian Herzmann, Christian K. Holm, Holger Heine, Athma Pai, Aisling O’Hara Hall, Kasper Hoebe, Katherine A. Fitzgerald |
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| Rok vydání: | 2022 |
| Předmět: |
Inflammation
Cell Proliferation/genetics Multidisciplinary Nuclear Receptor Subfamily 4 Group A Member 2/genetics Cell Movement Inflammation/genetics Nuclear Receptor Subfamily 4 Group A Member 2 Cell Movement/genetics Humans Receptors Cytoplasmic and Nuclear RNA Long Noncoding RNA Long Noncoding/genetics Cell Proliferation |
| Zdroj: | Vierbuchen, T, Agarwal, S, Johnson, J L, Galia, L, Lei, X, Stein, K, Olagnier, D, Gaede, K I, Herzmann, C, Holm, C K, Heine, H, Pai, A, O'Hara Hall, A, Hoebe, K & Fitzgerald, K A 2023, ' The lncRNA LUCAT1 is elevated in inflammatory disease and restrains inflammation by regulating the splicing and stability of NR4A2 ', Proceedings of the National Academy of Sciences of the United States of America, vol. 120, no. 1, pp. e2213715120 . https://doi.org/10.1073/pnas.2213715120 |
| ISSN: | 1091-6490 |
| DOI: | 10.1073/pnas.2213715120 |
| Popis: | The nuclear long non-coding RNA LUCAT1 has previously been identified as a negative feedback regulator of type I interferon and inflammatory cytokine expression in human myeloid cells. Here, we define the mechanistic basis for the suppression of inflammatory gene expression by LUCAT1. Using comprehensive identification of RNA-binding proteins by mass spectrometry as well as RNA immunoprecipitation, we identified proteins important in processing and alternative splicing of mRNAs as LUCAT1-binding proteins. These included heterogeneous nuclear ribonucleoprotein C, M, and A2B1. Consistent with this finding, cells lacking LUCAT1 have altered splicing of selected immune genes. In particular, upon lipopolysaccharide stimulation, the splicing of the nuclear receptor 4A2 (NR4A2) gene was particularly affected. As a consequence, expression of NR4A2 was reduced and delayed in cells lacking LUCAT1. NR4A2-deficient cells had elevated expression of immune genes. These observations suggest that LUCAT1 is induced to control the splicing and stability of NR4A2, which is in part responsible for the anti-inflammatory effect of LUCAT1. Furthermore, we analyzed a large cohort of patients with inflammatory bowel disease as well as asthma and chronic obstructive pulmonary disease. In these patients, LUCAT1 levels were elevated and in both diseases, positively correlated with disease severity. Collectively, these studies define a key molecular mechanism of LUCAT1-dependent immune regulation through post-transcriptional regulation of mRNAs highlighting its role in the regulation of inflammatory disease. |
| Databáze: | OpenAIRE |
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