The long non-coding RNA LUCAT1 is a negative feedback regulator of interferon responses in humans

• Published in: Nature communications Vol. 11; no. 1; pp. 6348 - 11
• Main Authors: Agarwal, Shiuli, Vierbuchen, Tim, Ghosh, Sreya, Chan, Jennie, Jiang, Zhaozhao, Kandasamy, Richard K., Ricci, Emiliano, Fitzgerald, Katherine A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.12.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 14/32; 45/91; 49/15; 49/88; 49/90; 631/250; 631/250/262; Animal models; Animals; Biological activity; Biological Phenomena; Chromatin; Chromatin - metabolism; Cytokines - metabolism; Feedback; Gene deletion; Gene Expression Regulation; Gene Knockdown Techniques; Genes; Humanities and Social Sciences; Humans; Immune response; Immune system; Immunity, Innate - drug effects; Immunology; Immunoregulation; Inflammation; Inflammatory response; Innate immunity; Interferon; Interferons - metabolism; Life Sciences; Lipopolysaccharides; Lipopolysaccharides - adverse effects; Mice; multidisciplinary; Myeloid cells; Myeloid Cells - metabolism; Negative feedback; Non-coding RNA; Nuclei (cytology); Oxidoreductases Acting on CH-CH Group Donors; Proteins; Regulators; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Science; Science (multidisciplinary); Stat1 protein; STAT1 Transcription Factor - metabolism; THP-1 Cells; Transcription; Innate Immune Response; LncRNA; Interferon IFN
• DOI: 10.1038/s41467-020-20165-5
• ISSN: 2041-1723

Long non-coding RNAs are important regulators of biological processes including immune responses. The immunoregulatory functions of lncRNAs have been revealed primarily in murine models with limited understanding of lncRNAs in human immune responses. Here, we identify lncRNA LUCAT1 which is upregulated in human myeloid cells stimulated with lipopolysaccharide and other innate immune stimuli. Targeted deletion of LUCAT1 in myeloid cells increases expression of type I interferon stimulated genes in response to LPS. By contrast, increased LUCAT1 expression results in a reduction of the inducible ISG response. In activated cells, LUCAT1 is enriched in the nucleus where it associates with chromatin. Further, LUCAT1 limits transcription of interferon stimulated genes by interacting with STAT1 in the nucleus. Together, our study highlights the role of the lncRNA LUCAT1 as a post-induction feedback regulator which functions to restrain the immune response in human cells. lncRNAs are transcriptional regulators, but little is known of them functioning as negative feedback regulators of inflammation in humans. Here, the authors show that the human lncRNA LUCAT1 sequesters STAT1 to limit JAK/STAT signaling and the inflammatory response to viral infection or TLR stimulation in myeloid cells.