Journal Article

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

Gingras, Anne-Claude, Lant, Benjamin, Schertzberg, Michael, Derry, W. Brent, Go, Christopher, Abdelilah-Seyfried, Salim, Fraser, Andrew G., Ohashi, Yota, Koskimäki, Janne, Awad, Issam A., Girard, Romuald, Li, Yan, Dogra, Deepika, Chapman, Eric M., Yu, Bin

2019

Overview

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. Cerebral Cavernous Malformations (CCM) are often caused by mutations in CCM1/KRIT1. Here, Chapman et al. elegantly show that the CCM complex promotes apoptosis by regulating zinc homeostasis and storage via a conserved mechanism that likely generates the pathological defects observed in CCM.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/2 / 13/89 / 14/63 / 38/70 / 45/41 / 49/1 / 49/88 / 49/91 / 631/208/135 / 631/443/592/75/593/1370 / 631/80/82/23 / 631/80/86 / 64/11 / 64/116 / 64/60 / 82/58 / 96/34 / Ablation / Animals / Animals, Genetically Modified / Apoptosis / Apoptosis - physiology / Apoptosis - radiation effects / Apoptosis Regulatory Proteins - genetics / Apoptosis Regulatory Proteins - metabolism / Brain - pathology / Brain - surgery / Caenorhabditis elegans - physiology / Caenorhabditis elegans - radiation effects / Caenorhabditis elegans Proteins - genetics / Caenorhabditis elegans Proteins - metabolism / Cation Transport Proteins - metabolism / Deoxyribonucleic acid / Disease Models, Animal / DNA / DNA damage / Gene expression / Gene Expression Profiling / Genotoxicity / Hemangioma, Cavernous, Central Nervous System - genetics / Hemangioma, Cavernous, Central Nervous System - pathology / Hemangioma, Cavernous, Central Nervous System - surgery / Homeostasis / Humanities and Social Sciences / Humans / Intestine / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / KRIT1 Protein - genetics / KRIT1 Protein - metabolism / Kruppel-Like Transcription Factors - metabolism / Localization / MAP kinase / MAP Kinase Signaling System - physiology / Mice / Mitogen-Activated Protein Kinase 1 - metabolism / Mitogen-Activated Protein Kinase 7 - metabolism / multidisciplinary / Muscle Proteins - genetics / Muscle Proteins - metabolism / Mutagenesis / Mutation / Phosphorylation - physiology / Proteins / Science / Science (multidisciplinary) / Sequence Alignment / Zebrafish / Zebrafish Proteins - genetics / Zebrafish Proteins - metabolism / Zinc / Zinc - metabolism / Zinc transporter