Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

ZAKα Recognizes Stalled Ribosomes through Partially Redundant Sensor Domains

ABSTRACT: Impairment of ribosome function activates the MAPKKK ZAK, leading to activation of mitogen-activated protein (MAP) kinases p38 and JNK and inflammatory signaling. The mechanistic basis for activation of this ribotoxic stress response (RSR) re-mains completely obscure. We show that the long isoform of ZAK (ZAKα) directly associates with ribosomes by inserting its flexible C terminus into the ribosomal intersubunit space. Here, ZAKα binds helix14 of 18S ribosomal RNA (rRNA). An adjacent domainin ZAKa also probes the ribosome, and together, these sensor domains are critically required for RSR activation after inhibition of both the E-site, the peptidyl transferase center (PTC), and ribotoxinaction. Finally, we show that ablation of the RSR response leads to organismal phenotypes and decreased lifespan in the nematode Caenorhabditis elegans (C. elegans). Our findings yield mechanistic insight into how cells detect ribotoxic stress and provide experimental in vivo evidence for its physiological importance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE131201 | GEO | 2020/04/15

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

ROS-induced translation impairment underlies ZAK-mediated metabolic decline in obesity and aging

Project description:The ribotoxic stress response (RSR) denotes a signaling pathway in which the p38 and JNK-activating MAP3 kinase ZAK senses stalling and/or collision of ribosomes with unknown physiological implications. Here, we show that reactive oxygen species (ROS)-generating agents robustly trigger translational impairment and ZAK activation. As a testament to the physiological importance of this signaling pathway, zebrafish larvae deficient for the ZAK kinase are protected from ROS-induced pathology and death. Furthermore, livers of mice fed a ROS-generating and obesogenic diet accrue ZAK-activating and antioxidant-reversed ribosomal stalls and collisions. Highlighting a role for the RSR in metabolic regulation, ZAK knockout (KO) mice are protected from developing insulin resistance and liver steatosis under these conditions. Finally, aged chow-fed ZAK KO mice do not display the normal hallmarks of metabolic aging. In sum, our work highlights ROS-induced translational impairment as a physiological activation signal for ZAK that underlies metabolic adaptation in obesity and aging.

2023-10-23 | GSE235700 | GEO

Stalled ribosomes are signals for metabolic regulation by the ribotoxic stress response

Project description:Impairment of translation can lead to stalling and collision of ribosomes which constitute an activation platform for several ribosomal stress-surveillance pathways. Among these is the Ribotoxic Stress Response (RSR), where ribosomal sensing by the MAP3K ZAKa leads to activation of p38 and JNK kinases. Despite these insights, the physiological ramifications of ribosomal impairment and downstream RSR signaling remain elusive. Here we show that stalling of ribosomes is sufficient to activate ZAKa. In response to amino acid deprivation and full nutrient starvation, RSR impacts on the ensuing metabolic responses in cells, nematodes and mice. The RSR-regulated responses in these model systems include regulation of AMPK and mTOR signaling, survival under starvation conditions, stress hormone production and regulation of blood sugar control. In addition, ZAK-/- mice present with a lean phenotype. Our work highlights stalled ribosomes as metabolic signals and demonstrates a role for RSR signaling in metabolic regulation.

2022-11-16 | GSE205191 | GEO

ROS-induced ribosome stalling and collision underlies ZAKalpha-mediated metabolic decline in obesity and aging

Project description:The ribotoxic stress response (RSR) denotes a signaling pathway in which the p38 and JNK-activating MAP3 kinase ZAKalpha senses stalling and/or collision of ribosomes with unknown physiological implications. Here, we show that reactive oxygen species (ROS)-generating agents robustly trigger translational impairment and ZAKalpha activation. Underscoring the physiological importance of this signaling pathway, zebrafish larvae deficient for the ZAKalpha kinase are protected from ROS-induced pathology and death. Furthermore, livers of mice fed a ROS-generating and obesogenic diet exhibit ZAKalpha-activating changes in ribosomal elongation dynamics. Highlighting a role for the RSR in metabolic regulation, ZAK knockout (KO) mice are protected from developing high-fat diet-induced blood glucose intolerance and liver steatosis under these conditions. Finally, ZAK ablation slows animals from developing hallmarks of metabolic aging. In sum, our work highlights ROS-induced translational impairment as a physiological activation signal for ZAKalpha that underlies metabolic adaptation in obesity and aging.

2024-02-01 | PXD043071 | Pride

ROS-induced translation impairment underlies ZAK-mediated metabolic decline in obesity and aging

Project description:The ribotoxic stress response (RSR) denotes a signaling pathway in which the p38 and JNK-activating MAP3 kinase ZAKalpha senses stalling and/or collision of ribosomes with unknown physiological implications. Here, we show that reactive oxygen species (ROS)-generating agents robustly trigger translational impairment and ZAKalpha activation. As a testament to the physiological importance of this signaling pathway, zebrafish larvae deficient for the ZAKalpha kinase are protected from ROS-induced pathology and death. Furthermore, livers of mice fed a ROS-generating and obesogenic diet accrue ZAKalpha-activating and antioxidant-reversed ribosomal stalls and collisions. Highlighting a role for the RSR in metabolic regulation, ZAK knockout (KO) mice are protected from developing insulin resistance and liver steatosis under these conditions. Finally, aged chow-fed ZAK KO mice do not display the normal hallmarks of metabolic aging. In sum, our work highlights ROS-induced translational impairment as a physiological activation signal for ZAKalpha that underlies metabolic adaptation in obesity and aging.

2023-11-16 | GSE213774 | GEO

Poly-GR impairs translation elongation and increases ribotoxic stress response in C9ORF72-ALS/FTD

Project description:Hexanucleotide repeat expansion in the C9ORF72 gene is the most frequent inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Poly-GR is one of the most toxic dipeptide repeat (DPR) proteins translated from the RNA repeats. It has been shown to affect protein synthesis, but how this contributes to neurodegeneration is not clear. Here, we found that poly-GR inhibits global translation by perturbing translation elongation. We identified that the transcripts with relatively slow elongation rate tend to be further stalled by poly-GR in iPSC-differentiated neurons. This increases ribosome collision and ZAKα-mediated ribotoxic stress response (RSR), which elevates the phosphorylation of p38 and promotes cell death. Knockdown of ZAKα or pharmacological inhibition of p38 can ameliorate the GR toxicity, and improve the survival of C9ORF72-ALS/FTD patient-derived iPSC-neurons. Our study reveals molecular mechanism of poly-GR mediated toxicity on global translatome, and identifies RSR as a potential therapeutic target for C9ORF72-ALS/FTD.

2024-08-23 | GSE230127 | GEO

ZAK activation on colliding ribosomes triggers SAPK signaling pathways to regulate cell fate

Project description:Problems arising during translation of mRNAs lead to ribosome stalling and collisions with trailing ribosomes. These collisions are known to trigger a series of events including degradation of the stalled nascent polypeptide, decay of the problematic mRNAs, and ribosome rescue. However, the systemic cellular response of ribosome collision has not been explored. Here, we uncover a novel function for ribosome collisions in signal transduction. Using multiple translation elongation inhibitors and cellular stress conditions, we show that ribosome collisions activate both the SAPK (Stress Activated Protein Kinase) and GCN2-mediated cellular stress response pathways that lead to apoptosis and the integrated stress response (ISR), respectively. We further show that the MAPKKK ZAK functions as the sentinel for ribosome collisions, and ZAK is required for activation of both SAPKs p38/JNK and GCN2 signaling pathways. Selective ribosome profiling and biochemistry demonstrate that ZAK preferentially associates with the minimal unit of colliding ribosomes, the disome, inducing ZAK phosphorylation. While ZAK associates with elongating ribosomes under non-stressed conditions, activation of ZAK is specifically trigger by colliding ribosomes. Together, these results provide new insights into how perturbation of translational homeostasis, as read-out by colliding ribosomes, regulates cell fate.

2020-08-18 | GSE141459 | GEO

Initiation of a ZAKa-dependent Ribotoxic Stress Response by the Innate Immunity Endoribonuclease RNase L

Project description:RNase L is a regulated endoribonuclease in higher vertebrates that functions in antiviral innate immunity. Interferons induce OAS enzymes that sense double-stranded RNA of viral origin leading to synthesis of 2’,5’-oligoadenylate (2-5A) activators of RNase L. However, it is unknown precisely how RNase L modulates host transcriptome through its endoribonuclease activity. To isolate effects of RNase L from other effects of double-stranded RNA or virus, 2-5A was directly introduced into cells. Here we report that RNase L activation by 2-5A causes a ribotoxic stress response that requires the ribosome-associated MAP3K, ZAK. Subsequently, the stress-activated protein kinases (SAPK) JNK and p38 are phosphorylated. RNase L activation profoundly altered the transcriptome by widespread depletion of mRNAs associated with different cellular functions, but also by SAPK-dependent induction of inflammatory genes. Our findings show that 2-5A is a ribotoxic stressor that causes RNA damage through RNase L triggering a ZAK kinase cascade leading to proinflammatory signaling and apoptosis.

2024-03-01 | GSE253530 | GEO

Translation-coupled sensing and degradation of RNA-protein crosslinks [Ribo-Seq: dataset_2]

Project description:Reactive aldehydes are abundant cytotoxic metabolites, which challenge homoeostasis by crosslinking cellular macromolecules. Aldehyde-induced DNA-DNA crosslinks cause cancer and bone marrow failure in Fanconi anemia, while covalent DNA-protein crosslinks require proteolytic repair to prevent liver tumours and premature ageing. Whether RNA damage contributes to the toxicity of aldehydes and whether cells possess mechanisms to resolve RNA-protein crosslinks (RPCs) in particular is unknown. Studying the specific consequences of aldehyde-induced RNA damage is challenging due to confounding induction of DNA damage. Here, we establish photoactivatable ribonucleosides as a tractable model system to study aldehyde-mimicking RNA damage in the absence of DNA damage. We find that RNA crosslinking damage causes translational stress by stalling elongating ribosomes, which causes cell death upon ZAKα-dependent activation of the ribotoxic stress response (RSR) and GCN2-dependent activation of the integrated stress response (ISR). Moreover, we discover the principles of a translation-coupled cellular quality control mechanism that targets RPCs. Collisions between translating ribosomes and crosslinked mRNA-binding proteins trigger their ubiquitylation and subsequent proteasomal degradation. Our findings reveal RNA damage and RPC formation as a central aspect of aldehyde-induced toxicity and establish a framework to study the cellular responses to these threats in mechanistic detail.

2023-11-13 | GSE240135 | GEO

Translation-coupled sensing and degradation of RNA-protein crosslinks [Ribo-Seq: dataset_1]

2023-11-13 | GSE219055 | GEO

Molecular basis of mRNA delivery to the bacterial ribosome by bS1 protein and RNA polymerase

Project description:The initiation of translation begins with formation of a ribosome-mRNA complex. In bacteria, the 30S ribosomal subunit is recruited to many mRNAs through both base pairing with the Shine Dalgarno (SD) sequence and RNA-binding by ribosomal protein bS1. Translation can initiate on mRNAs that are being transcribed, and RNA polymerase (RNAP) can promote recruitment of the pioneering 30S. Here we have examined ribosome recruitment to mRNAs using cryogenic electron microscopy (cryo-EM), single-molecule fluorescence co-localization, and whole-cell cross-linking mass spectrometry. Structures of 30S-mRNA complexes show that bS1 delivers the mRNA to the ribosome for SD duplex formation and initial 30S subunit activation. RNAP associates flexibly with the 30S platform during nascent mRNA delivery and accelerates their association in a bS1-dependent manner in vitro. Collectively, our data provide a mechanistic framework for how the SD duplex, ribosomal proteins and RNAP cooperate in 30S recruitment to mRNAs and thereby establish transcription-translation coupling.

2024-11-15 | PXD048229 | JPOST Repository

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data