Eric M. Chapman, Benjamin Lant, Yota Ohashi, Bin Yu, Michael Schertzberg, Christopher Go, Deepika Dogra, Janne Koskimaki, Romuald Girard, Yan Li, Andrew G. Fraser, Issam A. Awad, Salim Abdelilah-Seyfried, Anne-Claude Gingras, William Brent Derry
- 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 andApoptotic 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.…
MetadatenAuthor details: | Eric M. Chapman, Benjamin Lant, Yota Ohashi, Bin Yu, Michael Schertzberg, Christopher Go, Deepika DograGND, Janne KoskimakiORCiD, Romuald Girard, Yan LiORCiD, Andrew G. Fraser, Issam A. Awad, Salim Abdelilah-SeyfriedORCiDGND, Anne-Claude GingrasORCiD, William Brent DerryORCiD |
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DOI: | https://doi.org/10.1038/s41467-019-09829-z |
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ISSN: | 2041-1723 |
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Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/30996251 |
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Title of parent work (English): | Nature Communications |
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Publisher: | Nature Publ. Group |
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Place of publishing: | London |
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Publication type: | Article |
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Language: | English |
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Date of first publication: | 2019/04/17 |
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Publication year: | 2019 |
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Release date: | 2021/03/02 |
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Volume: | 10 |
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Number of pages: | 15 |
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Funding institution: | Canadian Institutes of Health Research (CIHR)Canadian Institutes of Health Research (CIHR) [MOP 137089]; CIHR FoundationCanadian Institutes of Health Research (CIHR) [FDN 143301]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P01 NS092521]; Excellence cluster REBIRTH by Deutsche Forschungsgemeinschaft (DFG) [SFB958, SE2016/7-2, SE2016/10-1]; DZHK; Alexander Graham Bell Canada Graduate Scholarship from the Natural Sciences and Engineering Council of Canada; Terry Fox Foundation Strategic Training in Transdisciplinary Radiation Science Scholarship; Safadi Translational Fellowship; Sigrid Juselius FoundationSigrid Juselius Foundation |
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Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
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DDC classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
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Peer review: | Referiert |
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Publishing method: | Open Access / Gold Open-Access |
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| DOAJ gelistet |
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License (German): | CC-BY - Namensnennung 4.0 International |
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