Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

OAS1/RNase L executes 5’-triphosphate RNA-dependent tumor cell apoptosis

ABSTRACT: Cytoplasmic double-stranded RNA is sensed by RIG-I-like receptors (RLR) leading to induction of type-I interferons (IFN-I), proinflammatory cytokines and apoptosis in tumor cells. Here, we elucidate the differential signaling mechanisms leading to cytokine secretion and/or cell death induction upon stimulation with the bona fide RIG-I ligand 5’-triphosphate RNA (3p-RNA). We show that both outcomes are mediated by distinct dsRNA-receptor families with RLR being essential for cytokine production and IFN-mediating priming of effector pathways, but not apoptosis itself. Affinity purification followed by mass spectrometry revealed 3p-RNA-specific binding and activation of oligoadenylate synthetase 1/RNase L. RNase L-deficient cells were profoundly impaired in their ability to undergo apoptosis. Mechanistically, the concerted action of translational arrest triggered by RNase L and upregulation of NOXA was needed to deplete anti-apoptotic MCL-1 causing intrinsic apoptosis. Thus, 3p-RNA-induced apoptosis is a two-step process consisting of a RIG-I-dependent priming and a RNase L-dependent effector phase.

ORGANISM(S): Homo sapiens

PROVIDER: GSE150658 | GEO | 2021/05/12

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

OAS1/RNase L executes 5’-triphosphate RNA-dependent tumor cell apoptosis

Project description:OAS1/RNase L executes 5’-triphosphate RNA-dependent tumor cell apoptosis

| PRJNA633110 | ENA

Ubiquitination of DEAD-box RNA helicase DDX3X by TRIM25

Project description:Tripartite motif protein 25 (TRIM25) is an E3 ligase that ubiquitinates multiple substrates within the RLR signalling cascade and plays both RING (really interesting new gene)-dependent and RING-independent roles in RIG-I-mediated IFN induction. We report that the PRY-SPRY domain of TRIM25 interacts with the N-terminal extension (NTE) of DEAD-box helicase 3X (DDX3X), a host protein with multiple roles in RLR signalling. Gene reporter assays and knockdown studies reveal DDX3X and TRIM25 cooperate to activate the IFN- promoter following RIG-I activation independent of DDX3X’s catalytic activity. We also show that TRIM25 ubiquitinates DDX3X at several lysine residues in vitro and in cells.

2021-09-08 | PXD028122 | Pride

IRF3 and Smad3 binding regions in a basal-like breast cancer cell line, BT549 transfected with polyI:C.

Project description:The activation of RIG-I-like receptor (RLR) signaling in cancer cells is widely recognized as a critical cancer therapy method. The expected mechanism of RLR ligand-mediated cancer therapy involves the promotion of cancer cell death and strong induction of interferon (IFN)-β that affects the tumor microenvironment. We have recently shown that activation of RLR signaling in triple-negative breast cancer cells (TNBC) attenuates TGF-β signaling, which partly contributes to the promotion of cancer cell pyroptosis. However, the consequences of suppression of TGF-β signaling by RLR ligands with respect to IFN-β-mediated tumor suppression are not well characterized. This study showed that cytosolic induction of a typical RLR ligand polyI:C in cancer cells produces significant levels of IFN-β, which inhibits the growth of the surrounding cancer cells. In addition, IFN-β-induced cell cycle arrest in surrounding cancer cells was inhibited by the expression of constitutively active Smad3 (caSmad3). caSmad3 suppresses IFN-β expression through the alleviation of IRF3 binding to the canonical target genes, as suggested by ChIP-seq analysis. Based on these findings, a new facet of the pro-tumorigenic function of TGF-β that suppresses IFN-β expression is suggested when exploiting RLR-mediated cancer treatment in TNBC.

2021-12-16 | GSE178830 | GEO

IRF3 binding regions in a basal-like breast cancer cell line, BT549 cells with Smad3 gene inactivation, transfected with polyI:C.

2021-12-16 | GSE188457 | GEO

The RIG-I like receptor LGP2 inhibits Dicer-dependent processing of long double-stranded RNA and blocks RNA interference in mammalian cells.

Project description:In vertebrates, the presence of viral RNA in the cytosol is sensed by members of the RIG-I like receptor (RLR) family , which signal to induce production of type I interferons (IFN). These key anti-viral cytokines act in a paracrine and autocrine manner to induce hundreds of interferon-stimulated genes (ISGs), whose protein products restrict viral entry, replication and budding. ISGs include the RLRs themselves: RIG-I, MDA5 and the least-studied family member, LGP2. In contrast, the IFN system is absent in plants and invertebrates, which defend themselves from viral intruders using RNA interference (RNAi). In RNAi, the endoribonuclease Dicer cleaves virus-derived double stranded RNA (dsRNA) into small interfering RNAs (siRNAs) that target complementary viral RNA for cleavage. Interestingly, the RNAi machinery is conserved in mammals and we have recently demonstrated that it is able to participate in mammalian antiviral defence in conditions in which the IFN system is suppressed. In contrast, when the IFN system is active, one or more ISGs act to mask or suppress antiviral RNAi. Here, we demonstrate that LGP2 constitutes one of the ISGs that can inhibit antiviral RNAi in mammals. We identify Dicer as an LGP2-associated protein and show that LGP2 inhibits Dicer cleavage of dsRNA into siRNAs both in vitro and in vivo. Further, we show that in cells lacking an IFN response, ectopic expression of LGP2 interferes with RNAi-dependent suppression of gene expression. Thus, the inefficiency of RNAi as a mechanism of antiviral defence in mammalian somatic cells can be in part attributed to Dicer inhibition by LGP2 induced by type I IFNs.

2018-01-17 | PXD008364 | Pride

A systems approach reveals MAVS signaling in myeloid cells as critical in resistance to Ebola virus in murine models of infection

Project description:The unprecedented 2013-16 outbreak of Ebola virus (EBOV) in West Africa resulted in over 11,300 human deaths. Host resistance to EBOV is thought to involve RIG-I-like receptor (RLR) signaling through the adaptor protein, mitochondrial antiviral signaling (MAVS), but role of RLR-MAVS in orchestrating anti-EBOV responses in vivo is not known. Here, we apply a systems approach to MAVS-deficient mice infected with either wild-type or mouse-adapted EBOV. MAVS controlled EBOV replication through expression of IFNα, IFN-stimulated genes, and regulation of inflammatory responses in the spleen, and prevented cell death in the liver, with macrophages implicated as a major cell-type influencing host resistance. A dominant role for RLR signaling in macrophages was confirmed following conditional deletion of MAVS in LysM+ myeloid cells. These findings reveal tissue-specific transcriptional pathways controlled by RLR signaling in resistance to EBOV, and suggest that EBOV adaptation to cause disease in mice is linked in part to increased antagonism of RLR-dependent signaling.

2016-12-31 | GSE83309 | GEO

RIG-I and MDA5 fRIP during KSHV lytic reactivation

Project description:The RIG-I like receptors (RLRs) RIG-I and MDA5 are cytosolic RNA helicases best characterized as restriction factors for RNA viruses. However, evidence suggests RLRs participate in innate immune recognition of other pathogens, including DNA viruses. Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus and the etiological agent of Kaposi's sarcoma and primary effusion lymphoma (PEL). We demonstrate that RIG-I and MDA5 restrict KSHV lytic reactivation in PEL. By performing fRIP-Seq, we define the in vivo RLR substrates and demonstrate that RIG-I and MDA5-mediated restriction is facilitated exclusively by the recognition of host-derived RNAs.

2018-10-11 | GSE116650 | GEO

West Nile virus infection of human monocyte-derived dendritic cells

Project description:West Nile virus (WNV) is a neurotropic flavivirus and the leading cause of mosquito-borne encephalitis in the United States. Recent studies in humans have found that dysfunctional T cell responses strongly correlate with development of severe WNV neuroinvasive disease. However, the contributions of human dendritic cells (DCs) in priming WNV-specific T cell immunity remains poorly understood. Here, we demonstrate that human monocyte derived DCs (moDCs) support productive viral replication following infection with a pathogenic strain of WNV. Antiviral effector gene transcription was strongly induced during the log-phase viral growth, while secretion of type I interferons (IFN) occurred with delayed kinetics. Activation of RIG-I like receptor (RLR) or type I IFN signaling prior to log-phase viral growth significantly diminished viral replication, suggesting that early activation of antiviral programs can block WNV infection. In contrast to the induction of antiviral responses, WNV infection did not promote transcription or secretion of pro-inflammatory (IL-6, GM-CSF, CCL3, CCL5, CXCL9) or T cell modulatory cytokines (IL-4, IL-12, IL-15). There was also minimal induction of molecules associated with antigen presentation and T cell priming, including the co-stimulatory molecules CD80, CD86, and CD40. Functionally, WNV-infected moDCs dampened allogenic CD4 and CD8 T cell activation and proliferation. Combined, we propose a model where WNV subverts human DC activation to compromise priming of WNV-specific T cell immunity.

2019-09-06 | GSE136342 | GEO

UBR5 promotes antiviral immunity by disengaging the transcriptional brake on RIG-I like receptors

Project description:RIG-I like receptors (RLRs) are the major viral RNA sensors essential for the initiation of antiviral immune responses to numerous RNA viruses. RLRs are subjected to stringent transcriptional and posttranslational regulations, of which ubiquitination is one of the most important. However, the role of ubiquitination in RLR transcription is unknown. Here, we generated, screened 375 definite ubiquitin ligase knockout cell lines and identified UBR5 as a positive regulator of RLR transcription. UBR5 deficiency (UBR5-/-) reduced antiviral immune responses to RNA viruses, while increased viral replication in primary cells and mice. Ubr5-/- mice were more susceptible to lethal RNA virus infection than Ubr5+/+ littermates. Mechanistically, UBR5 mediated the Lysine 63-linked ubiquitination of TRIM28, an epigenetic repressor of RLRs. This modification prevented intramolecular SUMOylation of TRIM28, thus disengaged the TRIM28-imposed brake on RLR transcription. In sum, UBR5 enables rapid upregulation of RLR expression to boost antiviral immune responses by ubiquitinating and de-SUMOylating TRIM28.

2023-12-13 | GSE245604 | GEO

UBR5 promotes antiviral immunity by disengaging the transcriptional brake on RIG-I like receptors (RNA-Seq)

2023-12-13 | GSE245603 | GEO