1. A conserved CCM complex promotes apoptosis non-autonomously by regulating zinc homeostasis
- Author
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Issam A. Awad, Andrew G. Fraser, Bin Yu, Yota Ohashi, W. Brent Derry, Yan Li, Romuald Girard, Anne-Claude Gingras, Michael R Schertzberg, Salim Abdelilah-Seyfried, Deepika Dogra, Eric M Chapman, Christopher D. Go, Benjamin Lant, and Janne Koskimäki
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Scaffold protein ,Hemangioma, Cavernous, Central Nervous System ,Cerebrovascular disorders ,General Physics and Astronomy ,Muscle Proteins ,Apoptosis ,02 engineering and technology ,medicine.disease_cause ,Germline ,Animals, Genetically Modified ,Mice ,Phosphorylation ,lcsh:Science ,Zebrafish ,Cation Transport Proteins ,KRIT1 Protein ,Mitogen-Activated Protein Kinase 1 ,Mutation ,Multidisciplinary ,biology ,Chemistry ,Intracellular Signaling Peptides and Proteins ,Brain ,021001 nanoscience & nanotechnology ,Cell biology ,Zinc ,0210 nano-technology ,Cell signalling ,MAP Kinase Signaling System ,Science ,Kruppel-Like Transcription Factors ,chemistry.chemical_element ,Development ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,ddc:570 ,medicine ,Animals ,Humans ,Caenorhabditis elegans ,Caenorhabditis elegans Proteins ,Transcription factor ,Institut für Biochemie und Biologie ,Mitogen-Activated Protein Kinase 7 ,Gene Expression Profiling ,General Chemistry ,Zebrafish Proteins ,biology.organism_classification ,Disease Models, Animal ,030104 developmental biology ,Mutagenesis ,lcsh:Q ,Apoptosis Regulatory Proteins ,Sequence Alignment - 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., 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.
- Published
- 2019