IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v10y2019i1d10.1038_s41467-019-09829-z.html
   My bibliography  Save this article

A conserved CCM complex promotes apoptosis non-autonomously by regulating zinc homeostasis

Author

Listed:
  • Eric M. Chapman

    (University of Toronto
    The Hospital for Sick Children)

  • Benjamin Lant

    (The Hospital for Sick Children)

  • Yota Ohashi

    (University of Toronto)

  • Bin Yu

    (The Hospital for Sick Children)

  • Michael Schertzberg

    (University of Toronto)

  • Christopher Go

    (University of Toronto
    Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital)

  • Deepika Dogra

    (Potsdam University)

  • Janne Koskimäki

    (The University of Chicago Medicine)

  • Romuald Girard

    (The University of Chicago Medicine)

  • Yan Li

    (The University of Chicago)

  • Andrew G. Fraser

    (University of Toronto
    University of Toronto)

  • Issam A. Awad

    (The University of Chicago Medicine)

  • Salim Abdelilah-Seyfried

    (Potsdam University)

  • Anne-Claude Gingras

    (University of Toronto
    Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital)

  • W. Brent Derry

    (University of Toronto
    The Hospital for Sick Children)

Abstract

Apoptotic death of cells damaged by genotoxic stress requires regulatory input from surrounding tissues. The C. elegans scaffold protein KRI-1, ortholog of mammalian KRIT1/CCM1, permits DNA damage-induced apoptosis of cells in the germline by an unknown cell non-autonomous mechanism. We reveal that KRI-1 exists in a complex with CCM-2 in the intestine to negatively regulate the ERK-5/MAPK pathway. This allows the KLF-3 transcription factor to facilitate expression of the SLC39 zinc transporter gene zipt-2.3, which functions to sequester zinc in the intestine. Ablation of KRI-1 results in reduced zinc sequestration in the intestine, inhibition of IR-induced MPK-1/ERK1 activation, and apoptosis in the germline. Zinc localization is also perturbed in the vasculature of krit1−/− zebrafish, and SLC39 zinc transporters are mis-expressed in Cerebral Cavernous Malformations (CCM) patient tissues. This study provides new insights into the regulation of apoptosis by cross-tissue communication, and suggests a link between zinc localization and CCM disease.

Suggested Citation

  • Eric M. Chapman & Benjamin Lant & Yota Ohashi & Bin Yu & Michael Schertzberg & Christopher Go & Deepika Dogra & Janne Koskimäki & Romuald Girard & Yan Li & Andrew G. Fraser & Issam A. Awad & Salim Abd, 2019. "A conserved CCM complex promotes apoptosis non-autonomously by regulating zinc homeostasis," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09829-z
    DOI: 10.1038/s41467-019-09829-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-019-09829-z
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-019-09829-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09829-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.