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

: Chapman EM, Lant B, Ohashi Y, Yu B, Schertzberg M, Go C, Dogra D, Koskimaki J, Girard R, Li Y, Fraser AG, Awad IA, Abdelilah-Seyfried S, Gingras AC, Derry WB

Publisher: NATURE PUBLISHING GROUP

: 2019

: Nature Communications

: NATURE COMMUNICATIONS

: NAT COMMUN

: ARTN 1791

: 10

: 15

: 2041-1723

DOI: https://doi.org/10.1038/s41467-019-09829-z

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.