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

ABSTRACT: Screening of the interacting molecular of AGO2 in mammals

ORGANISM(S): Homo Sapiens

SUBMITTER: Shumin Zhang

PROVIDER: PXD032854 | iProX | Mon Mar 28 00:00:00 BST 2022

REPOSITORIES: iProX

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

Zhang Shumin S Zhang Xuhua X Bie Yuanyuan Y Kong Jing J Wang An A Qiu Yang Y Zhou Xi X

Virologica Sinica 20220506 4

RNA interference (RNAi) is an intrinsic antiviral immune mechanism conserved in diverse eukaryotic organisms. However, the mechanism by which antiviral RNAi in mammals is regulated is poorly understood. In this study, we uncovered that the E3 ubiquitin ligase STIP1 homology and U-box-containing protein 1 (STUB1) was a new regulator of the RNAi machinery in mammals. We found that STUB1 interacted with and ubiquitinated AGO2, and targeted it for degradation in a chaperon-dependent manner. STUB1 pr ...[more]

PMID: 35533808

Similar Datasets

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

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

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

| PRJNA781958 | ENA

Hypoxia Regulates Overall mRNA Homeostasis by Inducing Met1-linked Linear Ubiquitination of AGO2 in Cancer Cells

Project description:Hypoxia is the most prominent feature in human solid tumors and induces activation of hypoxia-inducible factors and their downstream genes to promote cancer progression. However, whether and how hypoxia regulates overall mRNA homeostasis is unclear. Here we show that hypoxia inhibits global-mRNA decay in cancer cells. Mechanistically, hypoxia induces the interaction of AGO2 with HOIL-1L/HOIP, two crucial components of a linear ubiquitin chain assembly complex, which co-localizes with miRNA-induced silencing complex and in turn catalyzes AGO2 occurring Met1-linked linear ubiquitination (M1-Ubi). A series of biochemical experiments reveal that M1-Ubi of AGO2 restrains miRNA-mediated gene silencing. Moreover, combination analyses of the AGO2-associated mRNA transcriptome by RIP-Seq and the mRNA transcriptome by RNA-Seq confirm that AGO2 M1-Ubi interferes miRNA-targeted mRNA recruiting to AGO2, and thereby facilitates accumulation of global mRNAs. By this mechanism, short-term hypoxia may protect overall mRNAs and enhances stress tolerance, whereas long-term hypoxia in tumor cells results in serious changing the entire gene expression profile, which is a driving force in the dynamic process of cell malignant evolution.

2020-09-26 | GSE158601 | GEO

Hypoxia Regulates Overall mRNA Homeostasis by Inducing Met1-linked Linear Ubiquitination of AGO2 in Cancer Cells

Project description:Hypoxia is the most prominent feature in human solid tumors and induces activation of hypoxia-inducible factors and their downstream genes to promote cancer progression. However, whether and how hypoxia regulates overall mRNA homeostasis is unclear. Here we show that hypoxia inhibits global-mRNA decay in cancer cells. Mechanistically, hypoxia induces the interaction of AGO2 with HOIL-1L/HOIP, two crucial components of a linear ubiquitin chain assembly complex, which co-localizes with miRNA-induced silencing complex and in turn catalyzes AGO2 occurring Met1-linked linear ubiquitination (M1-Ubi). A series of biochemical experiments reveal that M1-Ubi of AGO2 restrains miRNA-mediated gene silencing. Moreover, combination analyses of the AGO2-associated mRNA transcriptome by RIP-Seq and the mRNA transcriptome by RNA-Seq confirm that AGO2 M1-Ubi interferes miRNA-targeted mRNA recruiting to AGO2, and thereby facilitates accumulation of global mRNAs. By this mechanism, short-term hypoxia may protect overall mRNAs and enhances stress tolerance, whereas long-term hypoxia in tumor cells results in seriously changing the entire gene expression profile to drive cell malignant evolution.

2021-04-06 | PXD021722 | iProX

IRTKS negatively regulates antiviral immunity through PCBP2 sumoylation-mediated MAVS degradation.

Project description: Not available

| S-EPMC4569712 | biostudies-literature

MicroRNAs reinforce repression of PRC2 transcriptional targets independently and through a feed-forward regulatory network with PRC2 [iCLIP]

Project description:We performed iCLIP for AGO2 to identify AGO2-interacting mRNAs in T98G glioblastoma multiforme cells.

2019-01-09 | GSE112651 | GEO

Antiviral RNA interference in mammalian cells

Project description:Plants and invertebrates protect themselves from viruses through RNA interference (RNAi), yet it remains unknown whether this defense mechanism exists in mammals. Antiviral RNAi involves the processing of viral long double-stranded (ds) RNA molecules into small interfering RNAs (siRNAs) by the ribonuclease (RNAse) III Dicer. These siRNAs are incorporated into effector complex(es) containing members of the Argonaute (Ago) protein family and guide silencing of complementary target viral RNAs. Here, we detect the accumulation of phased Dicer-dependent virus-derived siRNA (viRNAs) and demonstrate their loading into Ago2 after infection of mouse embryonic stem (ES) cells with Encephalomyocarditis virus (EMCV). We further show that the production of these viRNAs is drastically reduced, yet not completely abolished, if ES cells are first induced to differentiate before infection. Finally, we reveal that the mammalian virus Nodamura virus (NoV) encodes for a protein that counteracts such antiviral RNAi in ES cells supporting the existence of an effective RNAi-based immunity in mammals. Infection of wild-type or mutant mouse ES cells and analysis of small RNAs from total extracts or immunoprecipitated components of the RNAi pathway

2013-10-10 | E-GEOD-43153 | biostudies-arrayexpress

Ubiquitination and degradation of NF90 by Tim-3 inhibits antiviral innate immunity.

Project description: Not available

| S-EPMC8225388 | biostudies-literature

TRIM27 negatively regulates NOD2 by ubiquitination and proteasomal degradation.

Project description: Not available

| S-EPMC3400628 | biostudies-literature

TRIM24 facilitates antiviral immunity through mediating K63-linked TRAF3 ubiquitination.

Project description: Not available

| S-EPMC7336305 | biostudies-literature