The RNA helicase DDX39B activates FOXP3 RNA splicing to control T regulatory cell fate
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ABSTRACT:
PROVIDER: PRJNA608194 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11149286_1.fastq.gz | Fastqsanger.gz | |||
| SRR11149286_2.fastq.gz | Fastqsanger.gz | |||
| SRR11149287_1.fastq.gz | Fastqsanger.gz | |||
| SRR11149287_2.fastq.gz | Fastqsanger.gz | |||
| SRR11149288_1.fastq.gz | Fastqsanger.gz |
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Project description:Autoimmune disease is caused by environmental and genetic factors. Genetic factors associated with increased susceptibility to multiple sclerosis (MS), an autoimmune disease of the central nervous system, have been identified, but their mechanisms of action are incompletely understood.(Briggs, 2019) We previously established that the association between MS risk and the interleukin-7 receptor-a gene (IL7R) is mediated by alternative splicing of IL7R transcripts.(Gregory et al., 2007) This splicing is regulated by the RNA helicase DEAD Box Polypeptide 39B (DDX39B), which shows genetic and functional epistasis with IL7R in enhancing MS risk (Galarza-Munoz et al., 2017). Here we discover that DDX39B, which is also known by immunologists as BAT1 (Spies et al., 1989), impacts the expression of many genes likely to play roles in autoimmunity.(Allcock et al., 2001; Degli-Esposti et al., 1992) We show that DDX39B controls expression of Forkhead Box P3 (FOXP3), a master regulator of the development, maintenance and function of CD4+/CD25+ T regulatory cells(Georgiev et al., 2019; Josefowicz et al., 2012) and repressor of autoimmunity (Bennett et al., 2001; Brunkow et al., 2001; Chatila et al., 2000; Wildin et al., 2001). Splicing of FOXP3 introns, which belong to a new subclass of introns with C-rich polypyrimidine tracts, was exquisitely sensitive to DDX39B levels, making FOXP3 expression highly sensitive to the levels of this RNA helicase. Low DDX39B levels in primary human T regulatory cells lead to loss of regulatory gene expression and cytokine signatures and gain of effector ones. Given the importance of FOXP3 in autoimmunity, this work cements DDX39B as a critically important guardian of immune tolerance that can reduce autoimmune disease risk by regulating IL7R splicing and upregulating FOXP3.
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Project description:RNA unwinding by DExH-type helicases underlies most RNA metabolism and function. It remains unresolved if and how the basic unwinding reaction of helicases is regulated by auxiliary domains. We explored the interplay between the RecA and auxiliary domains of the RNA helicase maleless (MLE) from Drosophila, using a suite of structural and functional studies. We discovered that MLE exists in a dsRNA bound open conformation and the auxiliary dsRBD2 domain aligns the substrate RNA with the accessible helicase tunnel. In an ATP-dependent manner, dsRBD2 associates with the helicase module, leading to tunnel closure around ssRNA. Furthermore, our structures provide a rationale for blunt ended dsRNA unwinding and 3’-5’ translocation by MLE. Structure-based MLE mutations confirm the functional relevance of our model for RNA unwinding. Our findings contribute to our understanding of fundamental mechanics of auxiliary domains in DExH helicase MLE which serves as model for its human ortholog and potentially therapeutic target, DHX9/RHA.
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Project description:Role of RNA Helicase gene DDX41
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Project description:Years after the discovery that Dicer is a key enzyme in gene-silencing, the role of its helicase domain remains enigmatic. Here we show that this domain is critical for accumulation of certain endogenous small interfering RNAs (endo-siRNAs) in C. elegans. The domain is required for the production of the direct products of Dicer, or primary endo-siRNAs, and consequently, affects levels of downstream intermediates, the secondary endo-siRNAs. Consistent with the role of endo-siRNAs in silencing, their loss correlates with an increase in cognate mRNA levels. We find that the helicase domain of Dicer is not required for microRNA (miRNA) processing, or RNA interference following exposure to exogenous double-stranded RNA. Comparisons of wildtype and helicase-defective strains using deep-sequencing analyses show that the helicase domain is required by a subset of annotated endo-siRNAs, in particular, those associated with the slightly longer 26 nucleotide small RNA species containing a 5M-bM-^@M-^Y guanosine. We reintroduced either wildtype Dicer, or Dicer harboring a mutation (K39A) in it's helicase domain, into dcr-1(ok247) mutant worms via transgene rescue. We then used high-throughput sequencing to compare levels of small RNAs present in each of these strains.
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Project description:Nicotinamide adenine dinucleotide (NAD) "cap" recently discovered in bacteria could have similar functions as eukaryotic 7-methylguanine (m7G) "cap", which protects RNA 5'-terminus from degradation and mediates RNA interactions with proteins involved in its transportation, editing and translation. The only known 5'-NAD-RNA-interacting E. coli protein is Nudix superfamily hydrolase NudC which is responsible for this "cap" hydrolysis. We conducted the search for NudC-interacting proteins and discovered that in vivo and in vitro NudC interacts with RNA helicase DeaD. We also discovered using bacterial two hybrid system that N-terminal parts of both proteins are involved in this interaction, particularly the N-terminal domain and zinc finger motif of NudC and RecA1, RecA2 and dimerization domains of DeaD. Detailed investigation on the hydrolase interactome revealed NudC contacts with at least three proteins involved in formation of RNA degradosome complex, DeaD, Hfq and PNPase, under stress conditions raising the idea that NudC could also function within the RNA degradosome. On the other hand, NudC together with DeaD interacts with 70S ribosome proteins. Thus, NudC is closely related to protein synthesis in ribosomes. Finally, since at least six NudC-interacting partners are involved in cell stress response we think that the helicase could play important role by moduling the cell conditions in response to environment changes.
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Project description:Regulatory T cells have been shown to adopt a catabolic metabolic programme with increased capacity for fatty acid oxidation fuelled oxidative phosphorylation (OXPHOS). The role of Foxp3 in this metabolic shift is poorly understood. Here we show that Foxp3 was sufficient to induce a significant increase in the spare respiratory capacity of the cell, the extra OXPHOS capacity available to a cell to increased demands on energy in response to work. Foxp3-expressing cells were enhanced in their ability to utilise palmitate for respiration and in addition the activity of electron transport complexes I, II and IV were enhanced following Foxp3 expression. ATP was secreted by both T effector and regulatory T cells and was reduced by mitochondrial respiration inhibitors. Thus Foxp3 imparts a selective advantage in ATP generation capacity to the cell and may exploit this as a source of adenosine for functional immunomodulation. In order to explore possible mechanisms for these differences in metabolism we conducted a comparative quantitative proteomics study to compare the contribution of TGFβ and the transcription factor Foxp3 to the Treg proteome. We used quantitative mass spectrometry to examine differences between proteomes of nuclear and cytoplasmic Foxp3-containing T cells and Foxp3 positive iTreg and Foxp3 negative activated CD4 T cells in addition to human peripheral blood natural Treg. Gene set enrichment analysis of our proteomic datasets demonstrated that Foxp3 drives a significant up regulation of several members of the mitochondrial electron transport chain.
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Project description:RNA helicase DDX21 mediates nucleotide stress responses
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Project description:We grouped Foxp3+ cells from Foxp3 Timer reporter mice into Blue1, Blue2, Red1, and Red2, and sorted these cells according to their Timer fluorescence expression, and analysed the transcriptional profiles of those cells, comparing them with those of effector and naive T cells using RNA-seq. Foxp3 Timer reporter mice were sensitised by a hapten, and 5 days later, the draining LNs of the skin were analysed.
2018-07-10 | GSE89481 | GEO
Project description:DDX3X is a mammalian RNA helicase that regulates RNA metabolism, cancers, innate immunity and several RNA viruses. We discovered that herpes simplex virus 1, a nuclear DNA replicating virus, highjacks redirects DDX3X to the nuclear envelope where it surprisingly modulates the exit of newly assembled viral particles. DDX3X depletion also led to an accumulation of virions in intranuclear herniations. Mechanistically, we show that DDX3X physically and functionally interacts with the virally encoded nuclear egress complex at the inner nuclear membrane. DDX3X also bound to and stimulated the incorporation in mature particles of pUs3, a herpes kinase that promotes viral nuclear release across the outer nuclear membrane. Overall, the data highlights two unexpected roles for an RNA helicase during the passage of herpes simplex viral particles through the nuclear envelope. This reveals a highly complex interaction between DDX3X and viruses and provides new opportunities to target viral propagation.
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Project description:Foxp3 is the master transcription factor for the regulatory T cells (Tregs). Alternative splicing of human Foxp3 results in the expression of two isoforms: the full-length and an exon 2-deleted protein. Here, AlphaFold2 predictions and in vitro experiments demonstrate that the N-terminal domain of Foxp3 inhibits DNA binding by moving toward the C-terminus and that this movement is mediated by exon 2. Consequently, we find Foxp3∆2-bearing tTregs in the peripheral lymphoid organ are less sensitive to TCR due to the enhanced binding of Foxp3∆2 to the Batf promoter and are unsusceptible to IL-2. In contrast, among RORγt+ pTregs in the large intestine, Foxp3∆2 pTregs express much more RORγt-related genes conferring a competitive advantage. Together, our results reveal that alternative splicing of exon 2 generates a constitutively active form of Foxp3, which plays a differential role in regulating tTregs and pTregs homeostasis.
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