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

Area of Science:

• Cell Biology
• Genetics
• Developmental Biology

Background:

• Apoptotic cell death triggered by genotoxic stress relies on signals from neighboring tissues.
• The C. elegans scaffold protein KRI-1, a homolog of mammalian KRIT1/CCM1, is known to mediate DNA damage-induced apoptosis in the germline through a non-autonomous mechanism.

Purpose of the Study:

• To elucidate the cell non-autonomous mechanism by which KRI-1 regulates DNA damage-induced apoptosis.
• To investigate the role of KRI-1 in zinc transport and its connection to Cerebral Cavernous Malformations (CCM).

Main Methods:

• Investigated KRI-1 and CCM-2 complex formation in the intestine.
• Analyzed the regulation of the ERK-5/MAPK pathway and KLF-3 transcription factor activity.
• Examined the expression of the SLC39 zinc transporter gene zipt-2.3.
• Assessed the impact of KRI-1 ablation on zinc sequestration, IR-induced MPK-1/ERK1 activation, and germline apoptosis.
• Studied zinc localization in krit1-/- zebrafish and SLC39 transporter expression in CCM patient tissues.

Main Results:

• KRI-1 forms a complex with CCM-2 in the intestine, negatively regulating the ERK-5/MAPK pathway.
• This regulation allows KLF-3 to promote the expression of zipt-2.3, facilitating intestinal zinc sequestration.
• KRI-1 deficiency leads to reduced intestinal zinc, impaired IR-induced MPK-1/ERK1 activation, and germline apoptosis.
• Perturbed zinc localization was observed in zebrafish vasculature, and SLC39 transporters were mis-expressed in CCM patient tissues.

Conclusions:

• KRI-1, via intestinal zinc sequestration, plays a crucial role in cell non-autonomous regulation of apoptosis.
• The study establishes a novel link between zinc localization, cross-tissue communication, and the pathogenesis of Cerebral Cavernous Malformations (CCM).