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

Nat Commun. 2019 Apr 17;10(1):1791. doi: 10.1038/s41467-019-09829-z.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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*

Substances

  • Apoptosis Regulatory Proteins
  • Caenorhabditis elegans Proteins
  • Cation Transport Proteins
  • Intracellular Signaling Peptides and Proteins
  • KLF-3 protein, C elegans
  • KRI-1 protein, C elegans
  • KRIT1 Protein
  • Krit1 protein, mouse
  • Kruppel-Like Transcription Factors
  • Muscle Proteins
  • Zebrafish Proteins
  • krit1 protein, zebrafish
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 7
  • mpk-1 protein, C elegans
  • Zinc