ZFIN ID: ZDB-PUB-190422-3
A conserved CCM complex promotes apoptosis non-autonomously by regulating zinc homeostasis
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.
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.
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.