PUBLICATION
A conserved CCM complex promotes apoptosis non-autonomously by regulating zinc homeostasis
- Authors
- Chapman, E.M., Lant, B., Ohashi, Y., Yu, B., Schertzberg, M., Go, C., Dogra, D., Koskimäki, J., Girard, R., Li, Y., Fraser, A.G., Awad, I.A., Abdelilah-Seyfried, S., Gingras, A.C., Derry, W.B.
- ID
- ZDB-PUB-190422-3
- Date
- 2019
- Source
- Nature communications 10: 1791 (Journal)
- Registered Authors
- Abdelilah-Seyfried, Salim
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- 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*
- Disease Models, Animal
- Gene Expression Profiling
- Hemangioma, Cavernous, Central Nervous System/genetics
- Hemangioma, Cavernous, Central Nervous System/pathology*
- Hemangioma, Cavernous, Central Nervous System/surgery
- Humans
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism*
- KRIT1 Protein/genetics
- KRIT1 Protein/metabolism
- Kruppel-Like Transcription Factors/metabolism
- MAP Kinase Signaling System/physiology
- Mice
- Mitogen-Activated Protein Kinase 1/metabolism
- Mitogen-Activated Protein Kinase 7/metabolism
- Muscle Proteins/genetics
- Muscle Proteins/metabolism
- Mutagenesis
- Mutation
- Phosphorylation/physiology
- Sequence Alignment
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Zinc/metabolism*
- PubMed
- 30996251 Full text @ Nat. Commun.
Citation
Chapman, E.M., Lant, B., Ohashi, Y., Yu, B., Schertzberg, M., Go, C., Dogra, D., Koskimäki, J., Girard, R., Li, Y., Fraser, A.G., Awad, I.A., Abdelilah-Seyfried, S., Gingras, A.C., Derry, W.B. (2019) A conserved CCM complex promotes apoptosis non-autonomously by regulating zinc homeostasis. Nature communications. 10:1791.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping