ZAK activation on colliding ribosomes triggers SAPK signaling pathways to regulate cell fate
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA593553 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10587771.fastq.gz | Fastqsanger.gz | |||
| SRR10587772.fastq.gz | Fastqsanger.gz | |||
| SRR10587773.fastq.gz | Fastqsanger.gz | |||
| SRR10587774.fastq.gz | Fastqsanger.gz | |||
| SRR11569080.fastq.gz | Fastqsanger.gz |
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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
Project description:Ribosome collisions activate the ribotoxic stress response (RSR) mediated by the MAP3K ZAKα (ZAK), which in turn regulates downstream phosphorylation of the MAPKs JNK and p38 and cell fate consequences. Despite this critical role during cellular stress, a structural and mechanistic understanding of the ZAK-ribosome interaction and activation have remained elusive. Here, we combine biochemistry with cryo-electron microscopy (cryo-EM) to dissect ZAK interactions with ribosomes in various states both in vivo and in vitro. We identified regions of ZAK necessary for binding to ribosomes under normal and under stress-induced conditions. Moreover, we discovered how interactions between ZAK and the ribosomal protein RACK1 mediate ZAK activation by recognizing the collision-interface. Further, we provide insight into how this process can be negatively regulated to prevent constitutive ZAK activation. Characterizing novel variants as well as a known pathogenic variant of ZAK’s SAM domain supports a key role of this conserved domain in regulating kinase activity on and off the ribosome. Collectively, we show that ZAK directly binds at the collided ribosome interface giving molecular insight into kinase activity regulation at the ribosome.
2025-10-02 | GSE299329 | GEO
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
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
Project description: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.
2020-04-15 | GSE131201 | GEO
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
Project description:ZAK activation at the collided ribosome
| PRJNA1273921 | ENA
Project description:The goal of this experiment was the confirmation of ZAK as a covalent target of Ibrutinib by an affinity enrichment experiment with a linkable analogue of Ibrutinib.
2017-10-13 | PXD007638 | Pride
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
Project description:Ribosome stalling at problematic sequences in mRNAs leads to collisions that trigger a collection of quality control events including ribosome rescue, targeting the nascent polypeptide for decay (Ribosome-mediated Quality Control or RQC), and targeting of the mRNA for decay (No Go Decay or NGD). Using a reverse genetic screen in yeast, we identify Cue2 as the endonuclease that is recruited to stalled ribosomes to promote NGD. Following Cue2-mediated cleavage, ribosomes upstream of the cleavage site translate to the end of the truncated mRNA and are rescued by the Dom34:Hbs1 complex. We also show that the putative helicase Slh1 (part of the RQC Trigger or RQT complex) removes collided ribosomes behind the lead stalled ribosome and thereby reduces endonucleolytic cleavage by Cue2. The synergistic activities of Cue2 and Slh1 define two parallel pathways that allow cells to recognize and respond to ribosomes trapped on problematic mRNAs.
2019-06-25 | GSE129128 | GEO