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

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 Abdelilah-Seyfried, Anne-Claude Gingras and W. Brent Derry ()
Additional contact information
Eric M. Chapman: University of Toronto
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
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
Issam A. Awad: The University of Chicago Medicine
Salim Abdelilah-Seyfried: Potsdam University
Anne-Claude Gingras: University of Toronto
W. Brent Derry: University of Toronto

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-019-09829-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09829-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-09829-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().