Ribosome impairment regulates intestinal stem cell identity via ZAKɑ activation

Silva, Joana; Alkan, Ferhat; Ramalho, Sofia; Snieckute, Goda; Prekovic, Stefan; Garcia, Ana Krotenberg; Hernández-Pérez, Santiago; Kammen, Rob van der; Barnum, Danielle; Hoekman, Liesbeth; Altelaar, Maarten; Zwart, Wilbert; Suijkerbuijk, Saskia J.E.; Bekker‐Jensen, Simon; Faller, William J.

doi:10.1038/s41467-022-32220-4

Cited by 15 publications

(24 citation statements)

References 83 publications

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“…Among the relevant JNK targets is RXRα, the phosphorylation of which inhibits the PPARα complex and transcriptional activation of the Fgf21 gene ( 51 ). FGF21 is a metabolic stress-induced hormone that has beneficial effects on both insulin sensitivity and liver adiposity ( 66 ), and these effects are exacerbated in jnk -deleted mice ( 51 ). Conversely, mice defective for p38 activation in the myeloid compartment are defective for hepatic FGF21 production and sensitized to metabolic dysfunction when fed a high-fat diet ( 67 ).…”

Section: Discussionmentioning

confidence: 99%

ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging

Snieckute,

Ryder,

Vind

et al. 2023

Science

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The ribotoxic stress response (RSR) is a signaling pathway in which the p38- and c-Jun N-terminal kinase (JNK)–activating mitogen-activated protein kinase kinase kinase (MAP3K) ZAKα senses stalling and/or collision of ribosomes. Here, we show that reactive oxygen species (ROS)–generating agents trigger ribosomal impairment and ZAKα activation. Conversely, zebrafish larvae deficient for ZAKα are protected from ROS-induced pathology. Livers of mice fed a ROS-generating diet exhibit ZAKα-activating changes in ribosomal elongation dynamics. Highlighting a role for the RSR in metabolic regulation, ZAK-knockout mice are protected from developing high-fat high-sugar (HFHS) diet-induced blood glucose intolerance and liver steatosis. Finally, ZAK ablation slows animals from developing the hallmarks of metabolic aging. Our work highlights ROS-induced ribosomal impairment as a physiological activation signal for ZAKα that underlies metabolic adaptation in obesity and aging.

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Section: Discussionmentioning

confidence: 99%

ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging

Snieckute,

Ryder,

Vind

et al. 2023

Science

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“…As antibody-DT conjugates are currently used to treat certain cancer types (Frankel et al, 2002), the contribution of RSR and the NLRP1 inflammasome in their therapeutic effect warrants further investigation. In addition, given that ZAKα-driven RSR is conserved in rodents (Snieckute et al, 2022; Silva et al, 2022), the immunological consequence of DTA as an in vivo cell ablation tool should also be more carefully examined.…”

Section: Discussionmentioning

confidence: 99%

Corynebacterium diphtheriaecauses keratinocyte-intrinsic ribotoxic stress and NLRP1 inflammasome activation in a model of cutaneous diphtheria

Robinson

Toh

Firdaus

et al. 2023

Preprint

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NLRP1 is an innate immune sensor protein that activates inflammasome-driven pyroptotic cell death. Recent work demonstrates that human NLRP1 has evolved to sense viral infections. Whether and how human NLRP1 responds to other infectious agents is unclear. Here, and in a companion manuscript, we report that human NLRP1, as an integral component of the ribotoxic stress response (RSR), is activated by bacterial exotoxins that target human ribosome elongation factors EEF1 and EEF2, including Diphtheria Toxin (DT) from Corynebacterium diphtheriae, exotoxin A from Pseudomonas aeruginosa and sidI from Legionella pneumophila. In human keratinocytes, DT activates RSR kinases ZAKalpha, p38 and JNKs, upregulates a set of signature RSR transcripts and triggers rapid NLRP1-dependent pyroptosis. Mechanistically, these processes require 1) DtxR-mediated de-repression of DT production in the bacteria, as well as 2) diphthamide synthesis and 3) ZAKalpha/p38-driven NLRP1 phosphorylation in the host. In 3D human skin cultures, Corynebacterium diphtheriae infection disrupts barrier function and induces IL-1 driven inflammation. Pharmacologic inhibition of p38 and ZAKalpha suppresses keratinocyte pyroptosis and rescues barrier integrity of Corynebacterium diphtheriae-treated organotypic skin. In summary, these findings implicate RSR and the NLRP1 inflammasome in antibacterial innate immunity and might explain certain aspects of diphtheria pathogenesis.

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“…Assessment of the cellular metabolic function was carried out using Seahorse Bioscience XFe24 Analyzer (Agilent). Measurements in organoids were done as described previously by our group (15). For HCT116 cells, these were seeded at 25 000 cells/well and cultured in DNA was then precipitated by mixing samples with 1 volume of isopropanol, followed by an incubation at 4°C overnight, and centrifugation at 8000 rpm for 30 minutes at 4°C.…”

Section: Bioenergetics Analysismentioning

confidence: 99%

NAC-mediated ribosome localization regulates cell fate and metabolism in intestinal stem cells

Ramalho,

Alkan,

Prekovic

et al. 2024

Preprint

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Intestinal stem cells (ISCs) face the challenge of integrating metabolic demands with unique regenerative functions. Studies have shown an intricate interplay between metabolism and stem cell capacity, however it is still not understood how this process is regulated. Combining ribosome profiling and CRISPR screening in intestinal organoids, we show that RNA translation is at the root of this interplay. We identify the nascent polypeptide-associated complex (NAC) as a key mediator of this process, and show that it regulates ISC metabolism by relocalizing ribosomes to the mitochondria. Upon NAC inhibition, intestinal cells show decreased import of mitochondrial proteins, which are needed for oxidative phosphorylation, and, consequently, enable the cell to maintain a stem cell identity. Furthermore, we show that overexpression of NACα is sufficient to drive mitochondrial respiration and promote ISC identity. Ultimately, our results reveal the pivotal role of ribosome localization in regulating mitochondrial metabolism and ISC function.

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Ribosome impairment regulates intestinal stem cell identity via ZAKɑ activation

Cited by 15 publications

References 83 publications

ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging

ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging

Corynebacterium diphtheriaecauses keratinocyte-intrinsic ribotoxic stress and NLRP1 inflammasome activation in a model of cutaneous diphtheria

NAC-mediated ribosome localization regulates cell fate and metabolism in intestinal stem cells

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