Tristetraprolin specifically regulates the expression and alternative splicing of immune response genes in HeLa cells

• Published in: BMC immunology Vol. 20; no. 1; p. 13
• Main Authors: Tu, Yafang, Wu, Xiongfei, Yu, Fengyun, Dang, Jianzhong, Wang, Juan, Wei, Yaxun, Cai, Zhitao, Zhou, Zhipeng, Liao, Wenliang, Li, Lian, Zhang, Yi
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 02-05-2019; BioMed Central; BMC
• Subjects: Adaptor Proteins, Vesicular Transport - metabolism; Alternative splicing; Alternative Splicing - genetics; Analysis; Binding proteins; Binding sites; Cancer; Chemokines; Cytokines; Deoxyribonucleic acid; DNA; Extracellular Signal-Regulated MAP Kinases - genetics; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Gene regulation; Genetic aspects; Genetic regulation; Genomes; Health aspects; HeLa Cells; Human papillomavirus; Humans; Immune response; Immunity, Innate - genetics; Inflammation; Innate immunity; Interferon; Interferon Type I - genetics; Interferon Type I - metabolism; Kinases; Lymphocytes T; MAP kinase; Methods; NF-kappa B - genetics; NF-κB protein; Overexpression; Phosphorylation; Physiological aspects; Proteins; Receptors, Antigen, T-Cell - genetics; RNA, Messenger - genetics; RNA-binding protein; RNA-seq; Signal transduction; Signal Transduction - genetics; T cell receptors; Toll-like receptors; Transcription; Transcriptomes; Tristetraprolin - genetics; Tristetraprolin - metabolism; Tumor necrosis factor; Tumor Necrosis Factor-alpha - genetics; Tumor necrosis factor-TNF; ZFP36; Alternative splicing; ZFP36; Overexpression; RNA-seq; Gene expression
• ISSN: 1471-2172; 1471-2172
• DOI: 10.1186/s12865-019-0292-1

Tristetraprolin (TTP) is an RNA binding protein that plays a critical role in regulating proinflammatory immune responses by destabilizing target mRNAs via binding to their AU-rich elements (AREs) in the 3'-UTRs of mRNAs. A recent CLIP-seq study revealed that TTP-binding sites are enriched in the intronic regions of RNA. TTP is also a nuclear protein that exhibits putative DNA-binding activity. These features suggested that TTP might regulate gene transcription and/or alternative splicing of pre-mRNAs in the absence of stimulation.
To elucidate the regulatory pattern of TTP, we cloned and overexpressed the human TTP-encoding gene, ZFP36, in HeLa cells in the absence of inflammatory stimuli. The transcriptomes of the control and ZFP36-overexpressing cells were sequenced and subjected to analysis and validation. Upon ZFP36 overexpression, the expression of genes associated with innate immunity, including those in the type I interferon signaling pathway and viral response, were specifically upregulated, implying a transcriptional regulatory mechanism associated with the predicted DNA binding activity of TTP. TTP preferentially regulated the alternative splicing of genes involved in the positive regulation of the I-κB/NF-κB cascade and the TRIF-dependent toll-like receptor, MAPK, TNF, and T cell receptor signaling pathways.
Our findings indicated that TTP may regulate the immune response via the regulation of alternative splicing and potentially transcription, which greatly expands the current understanding of the mechanisms of TTP-mediated gene regulation.