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Endonucleolytic RNA cleavage drives changes in gene expression during the innate immune response.

ABSTRACT: Viral infection triggers several double-stranded RNA (dsRNA) sensors that lead to changes in gene expression in the cell. One of these sensors activates an endonuclease, ribonuclease L (RNase L), that cleaves single-stranded RNA. However, how the resultant widespread RNA fragmentation affects gene expression is not fully understood. Here, we show that this fragmentation induces the ribotoxic stress response via ZAKα, potentially through stalled ribosomes and/or ribosome collisions. The p38 and JNK pathways that are activated as part of this response promote outcomes that inhibit the virus, such as programmed cell death. We also show that RNase L limits the translation of stress-responsive genes. Intriguingly, we found that the activity of the generic endonuclease, RNase A, recapitulates many of the same molecular phenotypes as activated RNase L, demonstrating how widespread RNA cleavage can evoke an antiviral program.

SUBMITTER: Karasik A

PROVIDER: S-EPMC11251458 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature

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Endonucleolytic RNA cleavage drives changes in gene expression during the innate immune response.

Karasik Agnes A Lorenzi Hernan A HA DePass Andrew V AV Guydosh Nicholas R NR

Cell reports 20240531 6

Viral infection triggers several double-stranded RNA (dsRNA) sensors that lead to changes in gene expression in the cell. One of these sensors activates an endonuclease, ribonuclease L (RNase L), that cleaves single-stranded RNA. However, how the resultant widespread RNA fragmentation affects gene expression is not fully understood. Here, we show that this fragmentation induces the ribotoxic stress response via ZAKα, potentially through stalled ribosomes and/or ribosome collisions. The p38 and J ...[more]

PMID: 38823018

Similar Datasets

Endonucleolytic RNA cleavage drives changes in gene expression during the innate immune response.

Project description:Viral infection triggers several dsRNA sensors that lead to changes in gene expression in the cell. One of these sensors activates an endonuclease, RNase L, that cleaves single stranded RNA. However, how the resultant widespread RNA fragmentation affects gene expression is not fully understood. Here we show that this fragmentation induces the Ribotoxic Stress Response via ZAKα, potentially through ribosome collisions. The p38 and JNK pathways that are activated as part of this response promote outcomes that inhibit the virus, such as programmed cell death. We also show that RNase L limits the translation of stress-responsive genes, including antiviral IFIT mRNAs and GADD34 that encodes an antagonist of the Integrated Stress Response. Intriguingly, we found the activity of the generic endonuclease, RNase A, recapitulates many of the same molecular phenotypes as activated RNase L, demonstrating how widespread RNA cleavage can evoke an antiviral program.HighlightsActivated RNase L acts with dsRNA-sensing pathways to promote cell signalingRNA fragmentation induces transcription through ZAKα signalingActivation of RNase L modulates levels of eIF2α phosphorylation Translation of the GADD34 and IFIT mRNAs is inhibited by active RNase L.

| S-EPMC10491309 | biostudies-literature

Endonucleolytic RNA cleavage drives changes in gene expression during the innate immune response

Project description:During viral infection, several dsRNA sensors are activated in the cell and trigger changes in gene expression. One of these sensors activates a generic endonuclease, RNase L, that cleaves many types of RNA in the cell. However, how the resultant widespread RNA decay affects gene expression is not fully understood. Here we found that gene expression changes caused by activating dsRNA sensing pathways are tuned by RNase L activation, pointing to an intricate antiviral response where multiple inputs are integrated to create an optimized output. We show that RNA fragmentation induces the activation of the Ribotoxic Stress Response, potentially through ribosome collisions. The p38 and JNK pathways that are actuated as part of this response promote outcomes that likely inhibit the virus, such as programmed cell death. We also show that RNase L appears to limit the translation of genes that are regulated by another dsRNA-induced pathway, the Integrated Stress Response. Intriguingly, we found the activity of another generic endonuclease, RNase A, recapitulates many of the same molecular phenotypes as activated RNase L, demonstrating how widespread RNA cleavage events can directly evoke an antiviral program.

2024-04-30 | GSE244125 | GEO

Endonucleolytic RNA cleavage drives changes in gene expression during the innate immune response [ribosome profiling]

2024-04-30 | GSE244176 | GEO

Endonucleolytic RNA cleavage drives changes in gene expression during the innate immune response

Project description:Endonucleolytic RNA cleavage drives changes in gene expression during the innate immune response

| PRJNA1021271 | ENA

Endonucleolytic RNA cleavage drives changes in gene expression during the innate immune response [ribosome profiling]

Project description:Endonucleolytic RNA cleavage drives changes in gene expression during the innate immune response [ribosome profiling]

| PRJNA1021597 | ENA

Neisseria gonorrhoeae-derived heptose elicits an innate immune response and drives HIV-1 expression.

Project description:Clinical and epidemiological synergy exists between the globally important sexually transmitted infections, gonorrhea and HIV. Neisseria gonorrhoeae, which causes gonorrhea, is particularly adept at driving HIV-1 expression, but the molecular determinants of this relationship remain undefined. N. gonorrhoeae liberates a soluble factor that potently induces expression from the HIV-1 LTR in coinfected cluster of differentiation 4-positive (CD4(+)) T lymphocytes, but this factor is not a previously described innate effector. A genome-wide mutagenesis approach was undertaken to reveal which component(s) of N. gonorrhoeae induce HIV-1 expression in CD4(+) T lymphocytes. A mutation in the ADP-heptose biosynthesis gene, hldA, rendered the bacteria unable to induce HIV-1 expression. The hldA mutant has a truncated lipooligosaccharide structure, contains lipid A in its outer membrane, and remains bioactive in a TLR4 reporter-based assay but did not induce HIV-1 expression. Mass spectrometry analysis of extensively fractionated N. gonorrhoeae-derived supernatants revealed that the LTR-inducing fraction contained a compound having a mass consistent with heptose-monophosphate (HMP). Heptose is a carbohydrate common in microbes but is absent from the mammalian glycome. Although ADP-heptose biosynthesis is common among Gram-negative bacteria, and heptose is a core component of most lipopolysaccharides, N. gonorrhoeae is peculiar in that it effectively liberates HMP during growth. This N. gonorrhoeae-derived HMP activates CD4(+) T cells to invoke an NF-?B-dependent transcriptional response that drives HIV-1 expression and viral production. Our study thereby shows that heptose is a microbial-specific product that is sensed as an innate immune agonist and unveils the molecular link between N. gonorrhoeae and HIV-1.

| S-EPMC3690901 | biostudies-other

Bat STING drives IFN-beta production in anti-RNA virus innate immune response.

Project description:The ability of stimulator of interferon genes (STING) to activate interferon (IFN) responses during RNA virus infection has been demonstrated in different mammalian cells. Despite being the host of numerous RNA viruses, the role of STING in bats during RNA virus infection has not been elucidated. In this study, we identified and cloned the STING gene of the Brazilian free-tailed bat Tadarida brasiliensis (T. brasiliensis) and tested its ability to induce IFN-β by overexpressing and knocking down bat STING (BatSTING) in T. brasiliensis 1 lung (TB1 Lu) cells. In addition, we used green fluorescent protein (GFP)-labeled vesicular stomatitis virus (VSV) VSV-GFP as a model to detect the antiviral activity of BatSTING. The results showed that overexpression of STING in TB1 Lu cells stimulated by cGAS significantly inhibited RNA virus replication, and the antiviral activities were associated with its ability to regulate basal expression of IFN-β and some IFN stimulated genes (ISGs). We also found that BatSTING was able to be activated after stimulation by diverse RNA viruses. The results of TB1 Lu cells with STING deficiency showed that knockdown of BatSTING severely hindered the IFN-β response triggered by VSV-GFP. Based on this, we confirm that BatSTING is required to induce IFN-β expression during RNA virus infection. In conclusion, our experimental data clearly show that STING in bat hosts plays an irreplaceable role in mediating IFN-β responses and anti-RNA virus infection.

| S-EPMC10514486 | biostudies-literature

Both endonucleolytic and exonucleolytic cleavage mediate ITS1 removal during human ribosomal RNA processing.

Project description:Human ribosome production is up-regulated during tumorogenesis and is defective in many genetic diseases (ribosomopathies). We have undertaken a detailed analysis of human precursor ribosomal RNA (pre-rRNA) processing because surprisingly little is known about this important pathway. Processing in internal transcribed spacer 1 (ITS1) is a key step that separates the rRNA components of the large and small ribosomal subunits. We report that this was initiated by endonuclease cleavage, which required large subunit biogenesis factors. This was followed by 3' to 5' exonucleolytic processing by RRP6 and the exosome, an enzyme complex not previously linked to ITS1 removal. In contrast, RNA interference-mediated knockdown of the endoribonuclease MRP did not result in a clear defect in ITS1 processing. Despite the apparently high evolutionary conservation of the pre-rRNA processing pathway and ribosome synthesis factors, each of these features of human ITS1 processing is distinct from those in budding yeast. These results also provide significant insight into the links between ribosomopathies and ribosome production in human cells.

| S-EPMC3587827 | biostudies-other

NMD targets experience deadenylation during their maturation and endonucleolytic cleavage during their decay.

Project description:Premature stop codon-containing mRNAs can produce truncated and dominantly acting proteins that harm cells. Eukaryotic cells protect themselves by degrading such mRNAs via the Nonsense-Mediated mRNA Decay (NMD) pathway. The precise reactions by which cells attack NMD target mRNAs remain obscure, precluding a mechanistic understanding of NMD and hampering therapeutic efforts to control NMD. A key step in NMD is the decay of the mRNA, which is proposed to occur via several competing models including deadenylation, exonucleolytic decay, and/or endonucleolytic decay. We set out to clarify the relative contributions of these decay mechanisms to NMD, and to identify the role of key factors. Here, we modify and deploy single-molecule nanopore mRNA sequencing to capture full-length NMD targets and their degradation intermediates, and we obtain single-molecule measures of splicing isoform, cleavage state, and poly(A) tail length. We observe robust endonucleolytic cleavage of NMD targets in vivo that depends on the nuclease SMG-6 and we use the occurence of cleavages to identify several known NMD targets. We show that NMD target mRNAs experience deadenylation, but similar to the extent that normal mRNAs experience as they enter the translational pool. Furthermore, we show that a factor (SMG-5) that historically was ascribed a function in deadenylation, is in fact required for SMG-6-mediated cleavage. Our results support a model in which NMD factors act in concert to degrade NMD targets in animals via an endonucleolytic cleavage near the stop codon, and suggest that deadenylation is a normal part of mRNA (and NMD target) maturation rather than a facet unique to NMD. Our work clarifies the route by which NMD target mRNAs are attacked in an animal.

| S-EPMC10557752 | biostudies-literature

The ECRG4 cleavage product augurin binds the endotoxin receptor and influences the innate immune response during otitis media.

Project description:Otitis media (OM), the most common disease of childhood, is typically characterized by bacterial infection of the middle ear (ME). Prominent features of OM include hyperplasia of the ME mucosa, which transforms from a monolayer of simple squamous epithelium with minimal stroma into a full-thickness respiratory epithelium in 2-3 days after infection. Analysis of the murine ME transcriptome during OM showed down-regulation of the tumor suppressor gene Ecrg4 that was temporally related to mucosal hyperplasia and identified stromal cells as the primary ECRG4 source. The reduction in Ecrg4 gene expression coincided with the cleavage of ECRG4 protein to release an extracellular fragment, augurin. The duration of mucosal hyperplasia during OM was greater in Ecrg4 -/- mice, the number of infiltrating macrophages was enhanced, and ME infection cleared more rapidly. ECRG4-null macrophages showed increased bacterial phagocytosis. Co-immunoprecipitation identified an association of augurin with TLR4, CD14 and MD2, the components of the lipopolysaccharide (LPS) receptor. The results suggest that full-length ECRG4 is a sentinel molecule that potentially inhibits growth of the ME stroma. Processing of ECRG4 protein during inflammation, coupled with a decline in Ecrg4 gene expression, also influences the behavior of cells that do not express the gene, limiting the production of growth factors by epithelial and endothelial cells, as well as the activity of macrophages.

| S-EPMC9461705 | biostudies-literature

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