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Argonaute3-SF3B3 complex controls pre-mRNA splicing to restrain Type-2 immunity [RNA-seq: cultured cells]

ABSTRACT: Argonaute (AGO) proteins execute Micro-RNA (miRNA) mediated gene silencing. However it is currently debated whether all 4 mammalian AGO proteins (AGO1, AGO2, AGO3 and AGO4) are required for miRNA activity. To address this, we generated a mouse with deleted Ago1, Ago3 and Ago4 genes (Ago134), and found that these Argonaute proteins are completely redundant for miRNA biogenesis, miRNA homeostasis or miRNA function, a role that is carried out exclusively by AGO2. Instead, AGO1/3/4 are required to curtail the expansion of Type-2 adaptive immunity in mice via regulation of precursor-mRNA (pre-mRNA) splicing in CD4+ TH lymphocytes. Gain- and loss-of-function experiments demonstrate that nuclear AGO3 interacts directly with SF3B3, a component of the U2 spliceosome complex, to aid global mRNA splicing. Our work uncouples AGO1, AGO3 and AGO4 from miRNA-mediated RNAi, discovers a new AGO3:SF3B3 complex in the cellular nucleus, and reveals an underappreciated mechanism by which AGO proteins prevent hyper-inflammatory disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE243700 | GEO | 2024/10/31

REPOSITORIES: GEO

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Argonaute3-SF3B3 complex controls pre-mRNA splicing to restrain Type-2 immunity [miRNA-seq]

Project description:Argonaute (AGO) proteins execute Micro-RNA (miRNA) mediated gene silencing. However it is currently debated whether all 4 mammalian AGO proteins (AGO1, AGO2, AGO3 and AGO4) are required for miRNA activity. To address this, we generated a mouse with deleted Ago1, Ago3 and Ago4 genes (Ago134), and found that these Argonaute proteins are completely redundant for miRNA biogenesis, miRNA homeostasis or miRNA function, a role that is carried out exclusively by AGO2. Instead, AGO1/3/4 are required to curtail the expansion of Type-2 adaptive immunity in mice via regulation of precursor-mRNA (pre-mRNA) splicing in CD4+ TH lymphocytes. Gain- and loss-of-function experiments demonstrate that nuclear AGO3 interacts directly with SF3B3, a component of the U2 spliceosome complex, to aid global mRNA splicing. Our work uncouples AGO1, AGO3 and AGO4 from miRNA-mediated RNAi, discovers a new AGO3:SF3B3 complex in the cellular nucleus, and reveals an underappreciated mechanism by which AGO proteins prevent hyper-inflammatory disease.

2024-10-31 | GSE243916 | GEO

Argonaute3-SF3B3 complex controls pre-mRNA splicing to restrain Type-2 immunity [RNA-seq: dissected tissues]

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Arabidopsis AGO1 N-terminal extension acts as an essential hub for PRMT5 interaction and post-translational modifications

Project description:Plant ARGONAUTE (AGO) proteins play pivotal roles in gene expression regulation through small (s)RNA-guided mechanisms. Among the ten AGO proteins in Arabidopsis thaliana, AGO1 stands out as the main effector of post-transcriptional gene silencing. Intriguingly, a specific region of AGO1, its N-terminal extension (NTE), has gained prominence in recent studies linked to diverse regulatory functions, including subcellular localization, sRNA loading, and interactions with regulatory factors. In the realm of post-translational modifications (PTMs), little is known about arginine methylation in Arabidopsis AGOs. This study reveals a novel and intricate landscape of AGO1 methylation. Here, we have elucidated that NTEAGO1 undergoes symmetric arginine dimethylation on specific residues, and interacts with the methyltransferase PRMT5, which catalyzes its methylation. Notably, we observed that the lack of symmetric dimethylarginine has no discernible impact on AGO1's subcellular localization or miRNA loading capabilities. However, the absence of PRMT5 significantly alters the loading of a subgroup of sRNAs into AGO1 and reshapes the NTEAGO1 interactome. Importantly, our research extends beyond AGO1, illustrating that symmetric arginine dimethylation of NTEs is a common process across Arabidopsis AGOs, taking place in AGO1, AGO2, AGO3, and AGO5, deepening our understanding of PTMs in the intricate landscape of RNA-associated gene regulation.

2024-05-22 | PXD049971 | Pride

AGO4 Regulates Entry into Meiosis and Influences Silencing of Sex Chromosomes in the Male Mouse Germline

Project description:The four mammalian Argonaute family members are thought to share redundant functions in the microRNA pathway, yet only AGO2 possesses the catalytic "slicer" function required for RNA interference. Whether AGO1, AGO3, or AGO4 possess specialized functions remains unclear. Here, we Series_summary = show that AGO4 localizes to spermatocyte nuclei during meiotic prophase I, specifically at sites of asynapsis and in the transcriptionally silenced XY sub-domain, the sex body. We generated Ago4 knockout mice and show that Ago4-/- spermatogonia initiate meiosis early, resulting from premature induction of retinoic acid-response genes. During prophase I, the sex body assembles incorrectly in Ago4-/- mice, leading to disrupted meiotic sex chromosome inactivation (MSCI). This is associated with a dramatic loss of microRNAs, >20% of which arise from the X chromosome. Loss of AGO4 results in increased AGO3 in spermatocytes, indicating some degree of redundancy. Thus, AGO4 regulates meiotic entry and MSCI in mammalian germ cells, implicating small RNA pathways in these processes. mRNA transcripts were isolated and prepared using pachytene spermatocytes, pre-meiotic testes and other tissues from Ago4+/+ and Ago4-/- littermates and sequenced using Illumina HiSeq2000. small RNA transcripts were isolated and prepared using pachytene spermatocytes from adult Ago4+/+ and Ago4-/- littermates and sequenced using Illumina GAII.

2012-08-01 | E-GEOD-39652 | biostudies-arrayexpress

AGO4 Regulates Entry into Meiosis and Influences Silencing of Sex Chromosomes in the Male Mouse Germline

2012-08-01 | GSE39652 | GEO

miRNAs associated with the different human Argonaute proteins

Project description:microRNAs (miRNAs) are small non-coding RNAs that function in literally all cellular processes. miRNAs interact with Argonaute (Ago) proteins and guide them to specific target sites located in the 3’ untranslated region (UTR) of target mRNAs leading to translational repression and deadenylation-induced mRNA degradation. Most miRNAs are processed from hairpin-structured precursors by the consecutive action of the RNase III enzymes Drosha and Dicer. However, processing of miR-451 is Dicer-independent and cleavage is mediated by the endonuclease Ago2. Here we have characterized miR-451 sequence and structure requirements for processing as well as sorting of miRNAs into different Ago proteins. Pre-miR-451 appears to be optimized for Ago2 cleavage and changes result in reduced processing. In addition, we show that the mature miR-451 only associates with Ago2 suggesting that mature miRNAs are not exchanged between different members of the Ago protein family. Based on cloning and deep sequencing of endogenous miRNAs associated with Ago1-3, we do not find evidence for miRNA sorting in human cells. However, Ago identity appears to influence the length of some miRNAs, while others remain unaffected. Examination of miRNAs associated with endogenous human Ago1-4 in HeLa cells

2013-03-29 | E-GEOD-45506 | biostudies-arrayexpress

Argonaute Binding within 3’-Untranslated Regions Does Not Predict Gene Repression

Project description:Despite two decades of study, the full scope of RNAi in mammalian cells has remained obscure. Here we combine: 1) Knockout of argonaute (AGO) variants; 2) RNA sequencing analysis of gene expression changes; and 3) Enhanced Crosslinking Immunoprecipitation Sequencing (eCLIP-seq) using anti-AGO2 antibody to identify potential microRNA (miRNA) binding sites. We find that knocking out AGO1, AGO2, and AGO3 are necessary to achieve full impact on gene expression. eCLIP-seq reveals several hundred significant AGO2 associations within 3’-untranslated regions. The standard mechanism of miRNA action would suggest that these associations repress gene expression. Contrary to this expectation, associations between AGO and RNA are poorly correlated with gene repression in wild-type versus knockout cells. Many clusters are associated with increased gene expression in wild-type versus knock out cells, including the strongest cluster within the MYC 3’-UTR. Our results suggest that assumptions about miRNA action should be re-examined.

2020-05-27 | GSE146688 | GEO

Arabidopsis AGO3 predominantly recruits 24-nucleotide small RNAs to regulate epigenetic silencing [miRNA-seq]

Project description:AGO3 predominantly bound 24-nt sRNAs with 5â?? terminal adenine. The spectrum of AGO3-associated sRNAs was different from those bound to AGO2. By contrast, approximately 30% of AGO3-bound 24-nt sRNAs overlapped with those bound to AGO4 and over 60% of AGO3-associated 24-nt sRNA enriched loci were identical to those of AGO4. In addition, expression of AGO3 driven by AGO4 native promoter partially complemented AGO4 function and rescued DNA methylation defect in ago4-1 background. Examination of AGO3 and AGO2 bound small RNAs with/without salt stress.

2016-05-31 | E-GEOD-78088 | biostudies-arrayexpress

STUB1 regulates antiviral RNAi through inducing ubiquitination and degradation of Dicer and AGO2 in mammals

Project description:RNA interference (RNAi) is a cell-intrinsic antiviral defense conserved in diverse organisms. However, the mechanism by which mammalian antiviral RNAi is regulated is largely unknown. Herein, we uncover that STUB1, an E3 ubiquitin ligase, interacts with and ubiquitinates AGO2, the core component of RNAi pathway, resulting in the degradation of AGO2 via ubiquitin-proteasome system. Additionally, STUB1 can induce the degradation of the other mammalian AGO proteins including AGO1, AGO3, and AGO4. Our further study reveals that STUB1 also interacts with and mediates the ubiquitination of Dicer, the endoribonuclease responsible for siRNA or miRNA biogenesis, via K48-linked poly-ubiquitin, which induces the degradation of Dicer and its specialized form, termed antiviral Dicer (aviDicer) that usually expresses in stem cells. Loss of STUB1 upregulated Dicer and AGO2, thereby enhancing antiviral RNAi to effectively inhibit viral RNA replication in mammalian cells. In vivo, the STUB1 deficiency markedly enhanced the production of virus-derived siRNAs and elicited a potent antiviral effect against Enterovirus-A71 (EV-A71) infection in newborn mouse. Our findings demonstrate STUB1 as a novel negative regulator of RNAi by mediating the ubiquitination and degradation of Dicer and AGO proteins, and provide novel insights into the regulatory mechanism of antiviral RNAi in mammals.

2021-11-22 | GSE189203 | GEO

Arabidopsis AGO3 predominantly recruits 24-nucleotide small RNAs to regulate epigenetic silencing [Bisulfite-seq]

Project description:AGO3 predominantly bound 24-nt sRNAs with 5’ terminal adenine. The spectrum of AGO3-associated sRNAs was different from those bound to AGO2. By contrast, approximately 30% of AGO3-bound 24-nt sRNAs overlapped with those bound to AGO4 and over 60% of AGO3-associated 24-nt sRNA enriched loci were identical to those of AGO4. In addition, expression of AGO3 driven by AGO4 native promoter partially complemented AGO4 function and rescued DNA methylation defect in ago4-1 background.

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