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The RtcB RNA ligase is an essential component of the metazoan unfolded protein response.

ABSTRACT: RNA ligation can regulate RNA function by altering RNA sequence, structure and coding potential. For example, the function of XBP1 in mediating the unfolded protein response requires RNA ligation, as does the maturation of some tRNAs. Here, we describe a novel in vivo model in C. elegans for the conserved RNA ligase RtcB, and show that RtcB ligates the xbp 1 mRNA during the IRE 1 branch of the unfolded protein response. Without RtcB, protein stress results in the accumulation of unligated xbp-1 mRNA fragments, defects in the unfolded protein response, and decreased lifespan. RtcB also ligates endogenous pre tRNA halves, and RtcB mutants have defects in growth and lifespan that can be bypassed by expression of pre-spliced tRNAs. In addition, animals that lack RtcB have defects that are independent of tRNA maturation and the unfolded protein response. Thus, RNA ligation by RtcB is required for the function of multiple endogenous target RNAs including both xbp-1 and tRNAs. RtcB is uniquely capable of performing these ligation functions, and RNA ligation by RtcB mediates multiple essential processes in vivo.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE61733 | GEO | 2014/09/24

SECONDARY ACCESSION(S): PRJNA261970

REPOSITORIES: GEO

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The RtcB RNA ligase is an essential component of the metazoan unfolded protein response.

Project description:RNA ligation can regulate RNA function by altering RNA sequence, structure and coding potential. For example, the function of XBP1 in mediating the unfolded protein response requires RNA ligation, as does the maturation of some tRNAs. Here, we describe a novel in vivo model in C. elegans for the conserved RNA ligase RtcB, and show that RtcB ligates the xbp 1 mRNA during the IRE 1 branch of the unfolded protein response. Without RtcB, protein stress results in the accumulation of unligated xbp-1 mRNA fragments, defects in the unfolded protein response, and decreased lifespan. RtcB also ligates endogenous pre tRNA halves, and RtcB mutants have defects in growth and lifespan that can be bypassed by expression of pre-spliced tRNAs. In addition, animals that lack RtcB have defects that are independent of tRNA maturation and the unfolded protein response. Thus, RNA ligation by RtcB is required for the function of multiple endogenous target RNAs including both xbp-1 and tRNAs. RtcB is uniquely capable of performing these ligation functions, and RNA ligation by RtcB mediates multiple essential processes in vivo. 4 paired-end RNA-seq reads. Control worms have pre-spliced tRNAs, RtcB-null have mutated RtcB, +/- tunicamycin treatment

2014-09-24 | E-GEOD-61733 | biostudies-arrayexpress

Role of a cryptic tRNA gene operon in the recovery from translation stress

Project description:As compared to Eukaryotes, Bacteria have a reduced tRNA gene set encoding between 30 and 220 tRNAs, which are thought to act in concert for the maintenance of gene translation. Here we show that in some bacteria the tRNA gene set may be partitioned in a housekeeping sub-set that sustains translation, and an inducible one that is generally silent but can be largely induced to provide functionality under particular conditions. In the model cyanobacterium Anabaena sp. PCC 7120, the inducible set forms an operon encoding 23 functional tRNAs. Transcription of these tRNAs is induced by translation stress, i.e. by insults that impair translation, including antibiotics that target the ribosome. The operon is co-regulated with genes encoding proteins like the tRNA ligase RtcB and the stress-specific protein DpsA, probably involved in a response directed to protect the cell and recover translation. Common regulation suggests participation of operonic tRNAs in this response, although mechanistic issues remain to be determined. Similar long tRNA gene operons were found in species across major bacterial phyla and are shown to be distinct in many aspects from other operons that evolved by gene accretion.

2021-07-14 | GSE159215 | GEO

A 5’ tRNA-Ala derived small RNA regulates anti-fungal defense in plants

Project description:Apart from their primordial role in protein synthesis, tRNAs can be cleaved to produce tRNA-derived small RNAs (tsRNAs). The biological functions of tsRNAs in plants remain largely unknown. In this study, we developed RtcB-based RNA sequencing, a method that captures and distinguishes between 2’,3’-cyclic-phosphate (cP)-terminated RNAs and 3’-OH-terminated RNAs, and profiled 5’ tsRNAs and 5’ tRNA halves in Arabidopsis thaliana. We found that Arabidopsis 5’ tsRNAs and 5’ tRNA halves predominantly contain a cP at the 3’ end and require S-like RNase 1 (RNS1) and RNS3 for their production. One of the most abundant 5’ tsRNA, 5’ tsR-Ala, likely by associating with AGO1, negatively regulates Cytochrome P450 71A13 (CYP71A13) expression and camalexin biosynthesis to repress anti-fungal defense. 5’ tsR-Ala is downregulated upon fungal infection. Our study provides a global view of 5’ tsRNAs and 5’ tRNA halves in Arabidopsis and unravels an important role of a 5’ tsRNA in regulating anti-fungal defense.

2022-02-16 | GSE183560 | GEO

Human RNase L Employs a Signaling Mechanism to Arrest Translation

Project description:To identify small RNA cleaved by RNaseL, we captured intracellular RNA with 2'-3' cyclic phosphates by ligation an Illumina-compatible adaptor and the RNA ligase RtcB.

2017-08-24 | GSE100520 | GEO

Growth Optimized Aminoacyl-tRNA Synthetase Levels Prevent Maximal tRNA Charging

Project description:Summary Aminoacyl-tRNA synthetases (aaRSs) serve a dual role in charging tRNAs. Their enzymatic activities both provide protein synthesis flux and reduce uncharged tRNA levels. Although uncharged tRNAs can negatively impact bacterial growth, substantial concentrations of tRNAs remain deacylated even under nutrient-rich conditions. Here we show that tRNA charging in Bacillus subtilis is not maximized due to optimization of aaRS production during rapid growth, which prioritizes demands in protein synthesis over charging levels. The presence of uncharged tRNAs is alleviated by precisely tuned translation kinetics and the stringent response, both insensitive to aaRS overproduction but sharply responsive to underproduction, allowing for just-enough aaRS production atop a “fitness cliff”. Notably, we find that the stringent response mitigates fitness defects at all aaRS underproduction levels even without external starvation. Thus, adherence to minimal, flux-satisfying protein production drives limited tRNA charging and provides a basis for the sensitivity and setpoints of an integrated growth-control network.

2020-07-20 | GSE141389 | GEO

Engineered mischarged transfer RNAs for correcting pathogenic missense mutations [MSR-seq]

Project description:Missense mutations account for nearly 50% of pathogenic mutations in human genetic diseases, most lack effective treatments. Gene therapies, CRISPR-based gene editing, and RNA therapies including transfer RNA (tRNA) modalities are common strategies for potential treatments of genetic diseases. However, reported tRNA therapies are for nonsense mutations, how tRNAs can be engineered to correct missense mutations have not been explored. Here, we describe missense correcting tRNAs (mc-tRNAs) as a potential therapeutic modality for correcting pathogenic missense mutations. Mc-tRNAs are engineered tRNAs that are charged with one amino acid and read codons of another amino acid in translation in human cells. We first developed a series of fluorescence protein (FP)-based reporters that indicate successful correction of missense mutations via restoration of fluorescence signals. We engineered mc-tRNAs that effectively corrected Serine and Arginine missense mutations in the reporters and confirmed the amino acid substitution by protein mass spectrometry and mc-tRNA expression by tRNA sequencing. We examined the transcriptome response to the expression of mc-tRNAs and found some mc-tRNAs induced minimum transcriptomic changes. Furthermore, we applied an Arg-tRNAGln(CUG) mc-tRNA to rescue the autolytic activity of a pathogenic CAPN3 Arg-to-Gln mutant involved in limb-girdle muscular dystrophy type 2A. These results establish a versatile pipeline for mc-tRNA engineering and demonstrate the potential of mc-tRNA as an alternative therapeutic platform for the treatment of genetic disorders.

2024-01-04 | GSE236623 | GEO

Engineered mischarged transfer RNAs for correcting pathogenic missense mutations [mRNA-seq]

2024-01-04 | GSE236622 | GEO

The Differentiation and Stress Response Factor, XBP-1, Drives Multiple Myeloma Pathogenesis

Project description:Multiple myeloma (MM) evolves from highly prevalent premalignant condition termed Monoclonal Gammopathy of Undetermined Significance (MGUS). We report an MGUS-MM phenotype arising in transgenic mice with Emu-directed expression of the unfolded protein/ER stress response and plasma cell development spliced isoform factor XBP-1s. Emu-XBP-1s elicited elevated serum Ig and IL-6 levels, skin alterations and with advancing age, a significant proportion of Emu-xbp-1s transgenic mice develop features diagnostic of human MM including bone lytic lesions. Transcriptional profiles of Emu-xbp-1s B lymphoid and MM cells show aberrant expression of genes known to be dysregulated in human MM including Cyclin D1, MAF, MAFB, and APRIL. This genetic model coupled with documented frequent XBP-1s overexpression in human MM serve to implicate chronic XBP-1s dysregulation in the development of this common and lethal malignancy. Keywords: XBP-1, MGUS, multiple myeloma, transgenic mouse

2007-04-09 | GSE6980 | GEO

Caenorhabditis elegans

Project description:The RtcB RNA ligase is an essential component of the metazoan unfolded protein response.

| PRJNA261970 | ENA

Nutritional control of protein translation

Project description:Regulation of protein translation is a key feature of many biological processes. Global protein translation as well as translation at the codon level can be regulated by RNA modifications. These modifications are particularly enriched in tRNAs, where they represent an additional regulatory layer on top of the primary RNA sequence. In eukaryotes, levels of tRNA queuosinylation reflect the bioavailability of the precursor queuine, which is salvaged from the gut microbiota and absorbed in the intestine. We show here that reduced queuine supply results in a strong reduction of tRNA queuosinylation in various cultured human cell lines and mouse tissues. In addition, Dnmt2-dependent tRNA methylation is dynamically modulated by the presence or absence of queuine. Ribosome profiling showed that nutritionally determined queuosine-tRNA (Q-tRNA) levels control the translation speed of Q-tRNA decoded codons. Dysregulation of translation resulted in pronounced endoplasmic reticulum stress and activation of the unfolded protein response, which could be rescued by the addition of queuine. Together, these findings establish a direct link between nutrient availability and the decoding of the transcriptome, thus providing a new perspective in our understanding of translational regulation.

2018-08-06 | GSE102315 | GEO

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