The transcription factor Xrp1 is required for PERK-mediated antioxidant gene induction in Drosophila

Brown, Brian; Mitra, Sahana; Roach, Finnegan D; Vasudevan, Deepika; Ryoo, Hyung Don

doi:10.7554/elife.74047

Cited by 37 publications

(37 citation statements)

References 87 publications

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“…Our motif analysis revealed an enrichment for Xrp1/Irbp18 heterodimer binding site motifs in promoters of glutathione metabolism transcripts, suggesting a potential alternate regulator of this pathway during aging. Xrp1 has recently been shown to induce glutathione-S-transferases as part of the PERK-mediated unfolded protein response [41], corroborating our motif analysis results.…”

Section: Discussionsupporting

confidence: 88%

Discovery and Visualization of Age-dependent Patterns in the Diurnal Transcriptome of Drosophila

Sebastian

Fey²,

Morar³

et al. 2022

Preprint

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Many critical life processes are regulated by input from 24-hour external light/dark cycles, such as metabolism, cellular homeostasis, and detoxification. The circadian clock, which helps coordinate the response to these diurnal light/dark cycles, remains rhythmic across lifespan; however, rhythmic transcript expression is altered during normal aging. To better understand how aging impacts diurnal expression, we present an improved Fourier-based method for detecting and visualizing rhythmicity that is based on the relative power of the 24-hour period compared to other periods (RP24). We apply RP24 to transcript-level expression profiles from the heads of young (5-day) and old (55-day) Drosophila melanogaster, and reveal novel age-dependent rhythmicity changes that may be masked at the gene level. We show that core clock transcripts phase advance during aging, while most rhythmic transcripts phase delay. Transcripts rhythmic only in young flies tend to peak before lights on, while transcripts only rhythmic in old peak after lights on. We show that several pathways including glutathione metabolism, gain or lose coordinated rhythmic expression with age providing insight into possible mechanisms of age-onset neurodegeneration. Remarkably, we find that many pathways show very robust coordinated rhythms across lifespan, highlighting their putative roles in promoting neural health. We investigate statistically enriched transcription factor binding site motifs that may be involved in these rhythmicity changes.

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Section: Discussionsupporting

confidence: 88%

Discovery and Visualization of Age-dependent Patterns in the Diurnal Transcriptome of Drosophila

Sebastian

Fey²,

Morar³

et al. 2022

Preprint

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“…Knockdown of Xrp1 or Irbp18 rescues proteotoxic stress in RpS3/+ cells, suggesting that this feed-forward loop is essential for build-up of proteotoxic stress and to reduce the competitiveness of Rp/+ cells. We note that during the revision of this manuscript two other independent studies have reported relevant and complementary findings [ 46 , 47 ]. Nrf2 is also activated by proteotoxic stress and contributes to this feedback loop, either independently of p-eIF2α (as illustrated in Fig 6G ), or downstream of p-eIF2α.…”

Section: Discussionmentioning

confidence: 65%

Xrp1 and Irbp18 trigger a feed-forward loop of proteotoxic stress to induce the loser status

et al. 2021

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Cell competition induces the elimination of less-fit “loser” cells by fitter “winner” cells. In Drosophila, cells heterozygous mutant in ribosome genes, Rp/+, known as Minutes, are outcompeted by wild-type cells. Rp/+ cells display proteotoxic stress and the oxidative stress response, which drive the loser status. Minute cell competition also requires the transcription factors Irbp18 and Xrp1, but how these contribute to the loser status is partially understood. Here we provide evidence that initial proteotoxic stress in RpS3/+ cells is Xrp1-independent. However, Xrp1 is sufficient to induce proteotoxic stress in otherwise wild-type cells and is necessary for the high levels of proteotoxic stress found in RpS3/+ cells. Surprisingly, Xrp1 is also induced downstream of proteotoxic stress, and is required for the competitive elimination of cells suffering from proteotoxic stress or overexpressing Nrf2. Our data suggests that a feed-forward loop between Xrp1, proteotoxic stress, and Nrf2 drives Minute cells to become losers.

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“…Consistently, we found that overexpression of PERK leads to upregulation of Xrp1 expression ( S6 Fig ). In addition, recent studies have shown that overexpression of PERK or ATF4 upregulates Xrp1 [ 32 , 34 ]. These observations suggest that Xrp1 acts both upstream and downstream of the PERK-eIF2α axis in a positive feedback loop.…”

Section: Discussionmentioning

confidence: 99%

Cell competition is driven by Xrp1-mediated phosphorylation of eukaryotic initiation factor 2α

et al. 2021

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Cell competition is a context-dependent cell elimination via cell-cell interaction whereby unfit cells (‘losers’) are eliminated from the tissue when confronted with fitter cells (‘winners’). Despite extensive studies, the mechanism that drives loser’s death and its physiological triggers remained elusive. Here, through a genetic screen in Drosophila, we find that endoplasmic reticulum (ER) stress causes cell competition. Mechanistically, ER stress upregulates the bZIP transcription factor Xrp1, which promotes phosphorylation of the eukaryotic translation initiation factor eIF2α via the kinase PERK, leading to cell elimination. Surprisingly, our genetic data show that different cell competition triggers such as ribosomal protein mutations or RNA helicase Hel25E mutations converge on upregulation of Xrp1, which leads to phosphorylation of eIF2α and thus causes reduction in global protein synthesis and apoptosis when confronted with wild-type cells. These findings not only uncover a core pathway of cell competition but also open the way to understanding the physiological triggers of cell competition.

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The transcription factor Xrp1 is required for PERK-mediated antioxidant gene induction in Drosophila

Cited by 37 publications

References 87 publications

Discovery and Visualization of Age-dependent Patterns in the Diurnal Transcriptome of Drosophila

Discovery and Visualization of Age-dependent Patterns in the Diurnal Transcriptome of Drosophila

Xrp1 and Irbp18 trigger a feed-forward loop of proteotoxic stress to induce the loser status

Cell competition is driven by Xrp1-mediated phosphorylation of eukaryotic initiation factor 2α

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