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The regulation of ferroptosis by MESH1 through the activation of the integrative stress response.

Publication ,  Journal Article
Lin, C-C; Ding, C-KC; Sun, T; Wu, J; Chen, K-Y; Zhou, P; Chi, J-T
Published in: Cell Death Dis
July 22, 2021

All organisms exposed to metabolic and environmental stresses have developed various stress adaptive strategies to maintain homeostasis. The main bacterial stress survival mechanism is the stringent response triggered by the accumulation "alarmone" (p)ppGpp, whose level is regulated by RelA and SpoT. While metazoan genomes encode MESH1 (Metazoan SpoT Homolog 1) with ppGpp hydrolase activity, neither ppGpp nor the stringent response is found in metazoa. The deletion of Mesh1 in Drosophila triggers a transcriptional response reminiscent of the bacterial stringent response. However, the function of MESH1 remains unknown until our recent discovery of MESH1 as the first cytosolic NADPH phosphatase that regulates ferroptosis. To further understand whether MESH1 knockdown triggers a similar transcriptional response in mammalian cells, here, we employed RNA-Seq to analyze the transcriptome response to MESH1 knockdown in human cancer cells. We find that MESH1 knockdown induced different genes involving endoplasmic reticulum (ER) stress, especially ATF3, one of the ATF4-regulated genes in the integrative stress responses (ISR). Furthermore, MESH1 knockdown increased ATF4 protein, eIF2a phosphorylation, and induction of ATF3, XBPs, and CHOP mRNA. ATF4 induction contributes to ~30% of the transcriptome induced by MESH1 knockdown. Concurrent ATF4 knockdown re-sensitizes MESH1-depleted RCC4 cells to ferroptosis, suggesting its role in the ferroptosis protection mediated by MESH1 knockdown. ATF3 induction is abolished by the concurrent knockdown of NADK, implicating a role of NADPH accumulation in the integrative stress response. Collectively, these results suggest that MESH1 depletion triggers ER stress and ISR as a part of its overall transcriptome changes to enable stress survival of cancer cells. Therefore, the phenotypic similarity of stress tolerance caused by MESH1 removal and NADPH accumulation is in part achieved by ISR to regulate ferroptosis.

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Published In

Cell Death Dis

DOI

EISSN

2041-4889

Publication Date

July 22, 2021

Volume

12

Issue

8

Start / End Page

727

Location

England

Related Subject Headings

  • Tunicamycin
  • Transcription, Genetic
  • Stress, Physiological
  • Pyrophosphatases
  • Phosphorylation
  • Neoplasm Proteins
  • Humans
  • Gene Knockdown Techniques
  • Ferroptosis
  • Endoplasmic Reticulum Stress
 

Citation

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Lin, C.-C., Ding, C.-K., Sun, T., Wu, J., Chen, K.-Y., Zhou, P., & Chi, J.-T. (2021). The regulation of ferroptosis by MESH1 through the activation of the integrative stress response. Cell Death Dis, 12(8), 727. https://doi.org/10.1038/s41419-021-04018-7
Lin, Chao-Chieh, Chien-Kuang Cornelia Ding, Tianai Sun, Jianli Wu, Kai-Yuan Chen, Pei Zhou, and Jen-Tsan Chi. “The regulation of ferroptosis by MESH1 through the activation of the integrative stress response.Cell Death Dis 12, no. 8 (July 22, 2021): 727. https://doi.org/10.1038/s41419-021-04018-7.
Lin C-C, Ding C-KC, Sun T, Wu J, Chen K-Y, Zhou P, et al. The regulation of ferroptosis by MESH1 through the activation of the integrative stress response. Cell Death Dis. 2021 Jul 22;12(8):727.
Lin, Chao-Chieh, et al. “The regulation of ferroptosis by MESH1 through the activation of the integrative stress response.Cell Death Dis, vol. 12, no. 8, July 2021, p. 727. Pubmed, doi:10.1038/s41419-021-04018-7.
Lin C-C, Ding C-KC, Sun T, Wu J, Chen K-Y, Zhou P, Chi J-T. The regulation of ferroptosis by MESH1 through the activation of the integrative stress response. Cell Death Dis. 2021 Jul 22;12(8):727.

Published In

Cell Death Dis

DOI

EISSN

2041-4889

Publication Date

July 22, 2021

Volume

12

Issue

8

Start / End Page

727

Location

England

Related Subject Headings

  • Tunicamycin
  • Transcription, Genetic
  • Stress, Physiological
  • Pyrophosphatases
  • Phosphorylation
  • Neoplasm Proteins
  • Humans
  • Gene Knockdown Techniques
  • Ferroptosis
  • Endoplasmic Reticulum Stress