The transcription factor Xrp1 orchestrates both reduced translation and cell competition upon defective ribosome assembly or function

  1. Marianthi Kiparaki  Is a corresponding author
  2. Chaitali Khan
  3. Virginia Folgado-Marco
  4. Jacky Chuen
  5. Panagiotis Moulos  Is a corresponding author
  6. Nicholas E Baker  Is a corresponding author
  1. Albert Einstein College of Medicine, United States
  2. Alexander Fleming Biomedical Sciences Research Center, Greece

Abstract

Ribosomal Protein (Rp) gene haploinsufficiency affects translation rate, can lead to protein aggregation, and causes cell elimination by competition with wild type cells in mosaic tissues. We find that the modest changes in ribosomal subunit levels observed were insufficient for these effects, which all depended on the AT-hook, bZip domain protein Xrp1. Xrp1 reduced global translation through PERK-dependent phosphorylation of eIF2α. eIF2α phosphorylation was itself sufficient to enable cell competition of otherwise wild type cells, but through Xrp1 expression, not as the downstream effector of Xrp1. Unexpectedly, many other defects reducing ribosome biogenesis or function (depletion of TAF1B, eIF2, eIF4G, eIF6, eEF2, eEF1α1, or eIF5A), also increased eIF2α phosphorylation and enabled cell competition. This was also through the Xrp1 expression that was induced in these depletions. In the absence of Xrp1, translation differences between cells were not themselves sufficient to trigger cell competition. Xrp1 is shown here to be a sequence-specific transcription factor that regulates transposable elements as well as single-copy genes. Thus, Xrp1 is the master regulator that triggers multiple consequences of ribosomal stresses, and is the key instigator of cell competition.

Data availability

mRNA-Seq data were analyzed from datasets available from GEO with accession numbers GSE112864 and GSE124924. All other data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure 1, Figure 2, Figure 2-figure supplement 1, Figure 8-figure supplement 4, Figure 10 and Figure 10-figure supplement 1.

The following previously published data sets were used

Article and author information

Author details

  1. Marianthi Kiparaki

    Genetics Department, Albert Einstein College of Medicine, Bronx, United States
    For correspondence
    kiparaki@fleming.gr
    Competing interests
    The authors declare that no competing interests exist.
  2. Chaitali Khan

    Genetics Department, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Virginia Folgado-Marco

    Genetics Department, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jacky Chuen

    Genetics Department, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Panagiotis Moulos

    Alexander Fleming Biomedical Sciences Research Center, Vari, Greece
    For correspondence
    moulos@fleming.gr
    Competing interests
    The authors declare that no competing interests exist.
  6. Nicholas E Baker

    Department of Genetics, Albert Einstein College of Medicine, Bronx, United States
    For correspondence
    nicholas.baker@einsteinmed.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4250-3488

Funding

National Institute of General Medical Sciences (research project grant GM120451)

  • Nicholas E Baker

NIH Office of the Director (instrumentation grant S10OD023591)

  • Nicholas E Baker

National Cancer Institute (Cancer Center Support Grant P30CA013330)

  • Nicholas E Baker

Ministry of Economy & Development, Greece (Research Infrastructure Grant Bio-Imaging GR MIS 5002755)

  • Marianthi Kiparaki

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2022, Kiparaki et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,441
    views
  • 479
    downloads
  • 20
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Marianthi Kiparaki
  2. Chaitali Khan
  3. Virginia Folgado-Marco
  4. Jacky Chuen
  5. Panagiotis Moulos
  6. Nicholas E Baker
(2022)
The transcription factor Xrp1 orchestrates both reduced translation and cell competition upon defective ribosome assembly or function
eLife 11:e71705.
https://doi.org/10.7554/eLife.71705

Share this article

https://doi.org/10.7554/eLife.71705

Further reading

    1. Cell Biology
    Erli Jin, Jennifer K Briggs ... Matthew J Merrins
    Research Article

    Oscillations in insulin secretion, driven by islet Ca2+ waves, are crucial for glycemic control. Prior studies, performed with single-plane imaging, suggest that subpopulations of electrically coupled β-cells have privileged roles in leading and coordinating the propagation of Ca2+ waves. Here, we used three-dimensional (3D) light-sheet imaging to analyze the location and Ca2+ activity of single β-cells within the entire islet at >2 Hz. In contrast with single-plane studies, 3D network analysis indicates that the most highly synchronized β-cells are located at the islet center, and remain regionally but not cellularly stable between oscillations. This subpopulation, which includes ‘hub cells’, is insensitive to changes in fuel metabolism induced by glucokinase and pyruvate kinase activation. β-Cells that initiate the Ca2+ wave (leaders) are located at the islet periphery, and strikingly, change their identity over time via rotations in the wave axis. Glucokinase activation, which increased oscillation period, reinforced leader cells and stabilized the wave axis. Pyruvate kinase activation, despite increasing oscillation frequency, had no effect on leader cells, indicating the wave origin is patterned by fuel input. These findings emphasize the stochastic nature of the β-cell subpopulations that control Ca2+ oscillations and identify a role for glucokinase in spatially patterning ‘leader’ β-cells.

    1. Cell Biology
    Giuliana Giamundo, Daniela Intartaglia ... Ivan Conte
    Research Article

    Endosomes have emerged as major signaling hubs where different internalized ligand–receptor complexes are integrated and the outcome of signaling pathways are organized to regulate the strength and specificity of signal transduction events. Ezrin, a major membrane–actin linker that assembles and coordinates macromolecular signaling complexes at membranes, has emerged recently as an important regulator of lysosomal function. Here, we report that endosomal-localized EGFR/Ezrin complex interacts with and triggers the inhibition of the Tuberous Sclerosis Complex (TSC complex) in response to EGF stimuli. This is regulated through activation of the AKT signaling pathway. Loss of Ezrin was not sufficient to repress TSC complex by EGF and culminated in translocation of TSC complex to lysosomes triggering suppression of mTORC1 signaling. Overexpression of constitutively active EZRINT567D is sufficient to relocalize TSC complex to the endosomes and reactivate mTORC1. Our findings identify EZRIN as a critical regulator of autophagy via TSC complex in response to EGF stimuli and establish the central role of early endosomal signaling in the regulation of mTORC1. Consistently, Medaka fish deficient for Ezrin exhibit defective endo-lysosomal pathway, attributable to the compromised EGFR/AKT signaling, ultimately leading to retinal degeneration. Our data identify a pivotal mechanism of endo-lysosomal signaling involving Ezrin and its associated EGFR/TSC complex, which are essential for retinal function.