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Terminal uridyltransferase 7 regulates TLR4-triggered inflammation by controlling Regnase-1 mRNA uridylation and degradation

ABSTRACT: Terminal uridyltransferase 7 regulates TLR4-triggered inflammation by controlling Regnase-1 mRNA uridylation and degradation

PROVIDER: PRJNA561406 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10011564.fastq.gz	Fastqsanger.gz
	SRR10011565.fastq.gz	Fastqsanger.gz
	SRR10011566.fastq.gz	Fastqsanger.gz
	SRR10011567.fastq.gz	Fastqsanger.gz
	SRR10011568.fastq.gz	Fastqsanger.gz

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Terminal uridyltransferase 7 regulates TLR4-triggered inflammation by controlling Regnase-1 mRNA uridylation and degradation [TAIL-Seq]

Project description:Terminal uridyltransferase 7 regulates TLR4-triggered inflammation by controlling Regnase-1 mRNA uridylation and degradation [TAIL-Seq]

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Terminal uridyltransferase 7 regulates TLR4-triggered inflammation by controlling Regnase-1 mRNA uridylation and degradation.

Project description:Different levels of regulatory mechanisms, including posttranscriptional regulation, are needed to elaborately regulate inflammatory responses to prevent harmful effects. Terminal uridyltransferase 7 (TUT7) controls RNA stability by adding uridines to its 3' ends, but its function in innate immune response remains obscure. Here we reveal that TLR4 activation induces TUT7, which in turn selectively regulates the production of a subset of cytokines, including Interleukin 6 (IL-6). TUT7 regulates IL-6 expression by controlling ribonuclease Regnase-1 mRNA (encoded by Zc3h12a gene) stability. Mechanistically, TLR4 activation causes TUT7 to bind directly to the stem-loop structure on Zc3h12a 3'-UTR, thereby promotes Zc3h12a uridylation and degradation. Zc3h12a from LPS-treated TUT7-sufficient macrophages possesses increased oligo-uridylated ends with shorter poly(A) tails, whereas oligo-uridylated Zc3h12a is significantly reduced in Tut7-/- cells after TLR4 activation. Together, our findings reveal the functional role of TUT7 in sculpting TLR4-driven responses by modulating mRNA stability of a selected set of inflammatory mediators.

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Terminal uridyltransferase 7 regulates TLR4-triggered inflammation by controlling Regnase-1 mRNA uridylation and degradation

Project description:We revealed that the transcriptome of the mammalian cells under inflammatory status using RNA Sequencing (RNA-Seq). The transcriptome of BMDMs from wild-type and Tut7-/- was compared to baseline. The fold-change was presented by the logarithm of p-values to the base 2 and the significance was presented by the negative logarithm of that to the base 10. log2FC > +0.2 and log2FC < -0.2 indicate the increase of transcript levels by >20% and decreased by >20%, respectively. Among the 352 genes, 111 of them involving in innate immune response were downregulated in Tut7-/- cells.

2021-05-26 | GSE136161 | GEO

Terminal uridyltransferase 7 regulates TLR4-triggered inflammation by controlling Regnase-1 mRNA uridylation and degradation [TAIL-Seq]

Project description:We revealed that the transcriptome of the mammalian cells under inflammatory status using TAIL-Seq. The reads from wild-type and Tut7-/- BMDMs were mapped to RefSeq mm10 using HISAT2 and trimmed illumina adapter sequences. Finally, using the specific sequences, including Zc3h12a and Il6 to filter out the sequences, and linker-1 to extract the sequences we interested.

2021-05-26 | GSE164259 | GEO

Molecular basis for cytoplasmic RNA surveillance by uridylation-triggered decay in Drosophila

Project description:The post-transcriptional addition of nucleotides to the 3´ end of RNA regulates the maturation, function, and stability of RNA species in all domains of life. Here, we show that, in flies, 3´ terminal RNA uridylation triggers the processive, 3´-to-5´ exoribonucleolytic decay via the RNase II/R enzyme CG16940, a homolog of the human Perlman syndrome exoribonuclease Dis3l2. Together with the TUTase Tailor, dmDis3l2 forms the cytoplasmic, uridylation-triggered RNA processing (TRUMP) complex, that functionally cooperates in the degradation of structured RNA. RNA-immunoprecipitation and high-throughput sequencing reveals a variety of TRUMP complex substrates, including abundant non-coding RNA, such as 5S rRNA, tRNA, snRNA, snoRNA, and the essential RNase MRP, uncovering a key function of the TRUMP complex in the cytoplasmic quality control of RNA polymerase III transcripts. Together with high-throughput biochemical characterization of dmDis3l2 and bacterial RNase R our results imply a conserved molecular function of RNase II/R enzymes as 'readers' of destabilizing post-transcriptional marks - uridylation in eukaryotes and adenylation in prokaryotes - that play important roles in RNA surveillance.

2017-02-10 | GSE84466 | GEO

Molecular basis for cytoplasmic RNA surveillance by uridylation-triggered decay in Drosophila

Project description:Molecular basis for cytoplasmic RNA surveillance by uridylation-triggered decay in Drosophila

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RHBDL4-triggered downregulation of COPII adaptor protein TMED7 suppresses TLR4-mediated inflammatory signaling

Project description:The toll-like receptor 4 (TLR4) is a central regulator of innate immune signaling that primarily recognizes bacterial lipopolysaccharide (LPS) cell wall constituents to trigger cytokine secretion. We identify the intramembrane protease RHBDL4 as a negative regulator of TLR4 signaling. We show that RHBDL4-triggers the degradation of TLR4’s trafficking factor TMED7, a member of the p24 family of COPII adaptor proteins, which counteracts the transport of TLR4 to the cell surface. Besides TMED7, RHBDL4 cleaves a subset of related p24 cargo receptors, suggesting that this is a general protein abundance control mechanism to regulate the loading of specific secretory proteins into COPII vesicles. Notably, TLR4 activation by LPS mediates transcriptional upregulation of RHBDL4. Hence, TLR4 activation triggers an RHBDL4-dependent negative feedback loop to reduce the export of newly synthesized TLR4 molecules from the endoplasmic reticulum into COPII-coated vesicles. This secretory cargo tuning mechanism prevents the over-activation of TLR4-dependent signaling and consequently alleviates septic shock in a mouse model.

2024-01-09 | PXD045934 | Pride

Effect of loss of Regnase-1 and Regnase-3 on the transcriptional profile in mouse Lin–Sca1+Kit+ (LSK) cells

Project description:Regulation of lineage biases in hematopoietic stem and progenitor cells (HSPCs) is pivotal for balanced hematopoietic output. However, little is known about the mechanism behind lineage choice in HSPCs. Here, we show that mRNA decay factors Regnase-1 (Zc3h12a) and Regnase-3 (Zc3h12c) are critical for induction of myeloid lineage priming, restricting lymphoid differentiation in HSPCs. Regnase-1- and Regnase-3-mediated control of mRNA encoding Nfkbiz, a transcriptional and epigenetic regulator, was essential for balancing lymphoid/myeloid lineage output in HSPCs in vivo. Furthermore, single cell-assay for transposase-accessible chromatin sequencing (scATAC-seq) analysis revealed that Regnase-1 and Regnase-3 control the epigenetic landscape on myeloid-related gene loci in hematopoietic stem cells (HSCs) via Nfkbiz. Consistently, an antisense oligonucleotide designed to inhibit Regnase-1- and Regnase-3-mediated Nfkbiz mRNA degradation primed HSCs toward myeloid lineages by enhancing Nfkbiz expression. Collectively, the collaboration between post-transcriptional control and chromatin remodeling by the Regnase-1/Regnase-3-Nfkbiz axis governs lineage priming, instructing HSC lineage specification.

2024-02-09 | GSE228923 | GEO

Crosstalk between the RNA-binding proteins Regnase-1 and -3 shapes mast cell survival and cytokine expression

Project description:Post-transcriptional regulation of immune-related transcripts by RNA-binding proteins (RBPs) impacts immune cell responses, including mast cell functionality. Despite their importance in immune regulation, the functional role of most RBPs remains to be understood. By manipulating the expression of specific RBPs in murine mast cells, coupled with mass spectrometry and transcriptomic analyses, we found that the Regnase family of proteins acts as a potent regulator of mast cell physiology. Specifically, Regnase-1 is required to maintain basic cell proliferation and survival, while both Regnase-1 and -3 cooperatively regulate the expression of inflammatory transcripts upon activation, with Tnf being a primary target in both human and mouse cells. Further, Regnase-3 directly interacts with Regnase-1 in mast cells and is necessary to restrain Regnase-1 expression through the destabilization of its transcript. Overall, our study identifies protein interactors of endogenously expressed Regnase factors, characterizes the regulatory interplay between Regnase family members in mast cells, and establishes their role in the control of mast cell homeostasis and inflammatory responses.

2024-05-31 | PXD051849 | Pride

Immune homeostasis and regulation of the Interferon pathway require myeloid-derived Regnase-3

Project description:The RNase Regnase-1 is a master RNA regulator in macrophages and T cells that degrades cellular and viral RNA upon NF-kB signaling. The roles of the other Regnase family-members remain largely unknown. Here, we analyze Regnase-3 deficient mice, which develop hypertrophic lymph nodes. We used various mice with immune cell specific deletions of Regnase-3 to demonstrate that Regnase-3 acts specifically within myeloid cells. Regnase-3 deficiency systemically increased interferon signaling, which increased the proportion of immature B and innate immune cells and suppressed follicles and germinal center formation. Expression analysis revealed that Regnase-3 and Regnase-1 share protein degradation pathways. Nevertheless, Regnase-3 expression is specifically high in macrophages and transcriptionally controlled by interferon signaling. Although direct targets in macrophages remain unknown, Regnase-3 can bind, degrade and regulate mRNAs, such Zc3h12a encoding Regnase-1, in vitro. These data indicate that Regnase-3, like Regnase-1, is an RNase and essential for immune homeostasis, but has diverged as a key regulator for the interferon pathway in macrophages.

2019-04-05 | GSE129325 | GEO

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