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Inosine suppresses liver A-to-I RNA editing to promote cancer-associated cachexia in a riboswitch-like manner.

ABSTRACT: Cancer-associated cachexia (CAC) is a devastating syndrome and a major cause of morbidity and mortality in advanced cancer patients while liver is emerging as a key organ during CAC progression1. However, how tumor dysregulates liver function to promote CAC remains largely unknown. Here, we employ NMR spectrometry to detect that the elevation of 13C-inosine availability, attributed to the tumor-induced cytosolic 5'-nucleotidase II (NT5C2) protein accumulation, decreases the abundance of adenosine deaminase act on RNA 1 p150 isoform in a riboswitch-like manner. Intriguingly, reduced liver A-I mRNA editome enhances the stability of Cathepsin L mRNA to aggravate liver autophagy, triggering the secretion of serum amyloid A1, while CTSL-/- mice fail to develop cachectic phenotype upon inosine treatment. Strikingly, NT5C2 inhibitor CRCD2, a frontline leukemia treatment drug, greatly attenuates CAC progression. Conclusively, our finding reveals that inosine-mediated liver A-to-I mRNA editome alteration promotes CAC progression in a riboswitch-like manner, shedding light on the clinical applications for early CAC diagnosis and intervention.

ORGANISM(S): Mus musculus

PROVIDER: GSE262917 | GEO | 2026/04/21

REPOSITORIES: GEO

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Inosine suppresses liver A-to-I RNA editing to promote cancer-associated cachexia in a riboswitch-like manner

Project description:Cancer-associated cachexia (CAC) is a devastating syndrome and a major cause of morbidity and mortality in advanced cancer patients while liver is emerging as a key organ during CAC progression1. However, how tumor dysregulates liver function to promote CAC remains largely unknown. Here, we employ NMR spectrometry to detect that the elevation of 13C-inosine availability, attributed to the tumor-induced cytosolic 5'-nucleotidase II (NT5C2) protein accumulation, decreases the abundance of adenosine deaminase act on RNA 1 p150 isoform in a riboswitch-like manner. Intriguingly, reduced liver A-I mRNA editome enhances the stability of Cathepsin L mRNA to aggravate liver autophagy, triggering the secretion of serum amyloid A1, while CTSL-/- mice fail to develop cachectic phenotype upon inosine treatment. Strikingly, NT5C2 inhibitor CRCD2, a frontline leukemia treatment drug, greatly attenuates CAC progression. Conclusively, our finding reveals that inosine-mediated liver A-to-I mRNA editome alteration promotes CAC progression in a riboswitch-like manner, shedding light on the clinical applications for early CAC diagnosis and intervention.

2026-04-21 | GSE262782 | GEO

A dual T-box riboswitch in Enterococcus faecium binds two tRNAs

Project description:A set of small RNAs was identified in Vancomycin-resistant Enterococcus faecium, a leading cause of MDR infections. We described here the function of srn_2050, acting as a T-box riboswitch to regulate expression of downstream genes encoding the HisRS and AspRS aminoacyl-tRNA synthetases. Comparative RNAseq between Aus0004 and isogenic srn_2050 mutant identified the genes whose expression is impacted by the RNA. srn_2050 structure in its ‘off state’ was deciphered by in-line probing, containing T-box consensus sequences, a pseudoknot, a specifier loop and a terminator. Transcription binding assays between the riboswitch and either tRNAAsp or tRNAHis indicate that each deacylated tRNA interacts with the T-box. Their anticodons bind to a GACAC sequence within the specifier loop (GAC and CAC are Asp and His codons, respectively), whereas tRNATyr (UA/C-U) does not. A pioneering evaluation of E. faecium amino acid auxotrophy, with emphasis on E. faecium strain Aus0004, revealed auxotrophy for Histidine but not for Aspartic acid. Based on comparative growths and RNAseq between Aus004 and Aus004-srn2050, the riboswitch is shown essential for growth under aspartate starvation. This is the first example of a functional riboswitch in E. faecium with two overlapping codons allowing a dual tRNA-dependent regulation at transcriptional level.

2020-11-16 | GSE161499 | GEO

DANCE-MaP probing of the adenine riboswitch

Project description:We show that DANCE-MaP permits measurement of state-specific per-nucleotide reactivities, direct secondary structure PAIRs, and tertiary RINGs for RNA structural ensembles. Here, we demonstrate DANCE-MaP on the V. vulnificus add riboswitch.

2022-03-23 | GSE182552 | GEO

Inosine suppresses liver A-to-I RNA editing to promote cancer-associated cachexia in a riboswitch-like manner

Project description:Inosine suppresses liver A-to-I RNA editing to promote cancer-associated cachexia in a riboswitch-like manner

| PRJNA1093377 | ENA

Inosine suppresses liver A-to-I RNA editing to promote cancer-associated cachexia in a riboswitch-like manner.

Project description:Inosine suppresses liver A-to-I RNA editing to promote cancer-associated cachexia in a riboswitch-like manner.

| PRJNA1094904 | ENA

Another layer of complexity in Staphylococcus aureus methionine biosynthesis control: Unusual RNase III-driven T-box riboswitch cleavage determines met operon mRNA stability and decay

Project description:In Staphylococcus aureus, de novo methionine biosynthesis is regulated by a unique hierarchical pathway involving stringent-response controlled CodY repression in combination with a T-box riboswitch and RNA decay. The T-box riboswitch residing in the 5' untranslated region (met leader RNA) of the S. aureus metICFE-mdh operon controls downstream gene transcription upon interaction with uncharged methionyl-tRNA. met leader and metICFE-mdh (m)RNAs undergo RNase-mediated degradation in a process whose molecular details are poorly understood. Here, we determined the secondary structure of the met leader RNA and found the element to harbor, beyond other conserved T-box riboswitch structural features, a terminator helix which is a target for RNase III endoribonucleolytic cleavage. As the terminator is a thermodynamically highly stable structure, it also forms posttranscriptionally in met leader/ metICFE-mdh read-through transcripts. Cleavage by RNase III releases the met leader from metICFE-mdh mRNA and initiates RNase J-mediated degradation of the mRNA from the 5'-end. Of note, metICFE-mdh mRNA stability varies over the length of the transcript with a longer lifespan towards the 3'-end. Corresponding variations in protein levels led us to hypothesize that coordinated RNA decay represents another level in the hierarchical methionine biosynthesis control network to adjust methionine biosynthesis enzyme amounts to current metabolic requirements.

2021-02-18 | PXD022677 | Pride

Another layer of complexity in Staphylococcus aureus methionine biosynthesis control: Unusual RNase III-driven T-box riboswitch cleavage determines met operon mRNA stability and decay

2021-08-10 | PXD020619 | Pride

Iterative design of a NAND hybrid riboswitch by deep batch Bayesian optimization

Project description:The design of large genetic circuits requires genetic regulatory devices capable of performing complex logic operations. Hybrid riboswitches, synthetically enhanced compact RNA elements (<100 nucleotides) that form a tertiary structure with the ability to specifically bind two different target molecules, can be used to design genetic regulators that emulate Boolean logic. When inserted into the 5' UTR of an mRNA, these devices can regulate translation initiation upon specific binding of one or both ligands. The goal of this study is to design hybrid riboswitches that emulate Boolean NAND logic in yeast. We propose a novel machine learning-based design framework combining high-throughput in vivo screening and deep Bayesian optimization. Through an initial screening, we discovered a hybrid riboswitch with NAND behavior. Using batch Bayesian optimization with an ensemble neural network as surrogate, we further improve the NAND functionality of our hybrid riboswitch with respect to a performance score, thereby achieving near digital NAND behavior. With its focus on model-based and score-driven design, our proposed method can complement experiment driven approaches by allowing fine grained adaptation of functionality, including constructs sensitive to single nucleotide changes.

2026-02-16 | GSE293990 | GEO

DANCE-MaP probing of the adenine riboswitch

Project description:DANCE-MaP probing of the adenine riboswitch

| PRJNA756782 | ENA

Sequestration of a two-component response regulator by a riboswitch regulated non-coding RNA

Project description:Riboswitches are ligand-binding elements contained within the 5’ untranslated regions of bacterial transcripts, which generally regulate expression of downstream open reading frames. Here we show that in Listeria monocytogenes, a Vitamin B12-binding (B12) riboswitch controls expression of a non-coding regulatory RNA, Rli55. Rli55 in turn controls expression of the eut genes, which enable ethanolamine utilization and require B12 as a cofactor. Defects in ethanolamine utilization, or in its regulation by Rli55, significantly attenuate Listeria virulence in mice. Rli55 functions by sequestering the two-component response regulator, EutV via a EutV binding-site contained within the RNA. Thus Rli55 is a riboswitch-regulated member of the small group of regulatory RNAs that function by sequestering a protein and reveals a unique mechanism of signal integration in bacterial gene regulation.

2014-08-22 | GSE60363 | GEO

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