The cisd gene family regulates physiological germline apoptosis through ced-13 and the canonical cell death pathway in Caenorhabditis elegans

Skylar D. King, Chipo F. Gray, Luhua Song, Rachel Nechushtai, Tina L. Gumienny, Ron Mittler, Pamela A. Padilla*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Programmed cell death, which occurs through a conserved core molecular pathway, is important for fundamental developmental and homeostatic processes. The human iron–sulfur binding protein NAF-1/CISD2 binds to Bcl-2 and its disruption in cells leads to an increase in apoptosis. Other members of the CDGSH iron sulfur domain (CISD) family include mitoNEET/CISD1 and Miner2/CISD3. In humans, mutations in CISD2 result in Wolfram syndrome 2, a disease in which the patients display juvenile diabetes, neuropsychiatric disorders and defective platelet aggregation. The C. elegans genome contains three previously uncharacterized cisd genes that code for CISD-1, which has homology to mitoNEET/CISD1 and NAF-1/CISD2, and CISD-3.1 and CISD-3.2, both of which have homology to Miner2/CISD3. Disrupting the function of the cisd genes resulted in various germline abnormalities including distal tip cell migration defects and a significant increase in the number of cell corpses within the adult germline. This increased germ cell death is blocked by a gain-of-function mutation of the Bcl-2 homolog CED-9 and requires functional caspase CED-3 and the APAF-1 homolog CED-4. Furthermore, the increased germ cell death is facilitated by the pro-apoptotic, CED-9-binding protein CED-13, but not the related EGL-1 protein. This work is significant because it places the CISD family members as regulators of physiological germline programmed cell death acting through CED-13 and the core apoptotic machinery.

Original languageAmerican English
Pages (from-to)162-178
Number of pages17
JournalCell Death and Differentiation
Issue number1
StatePublished - 1 Jan 2019

Bibliographical note

Funding Information:
Acknowledgements This work is supported by a grant from the NSF IOS (1557787) to P.A.P. (PI) and R.M. (CoPI). We thank Ed Dzia-lowski and members of the Padilla lab for input. We thank WormBase, supported by grant U41 HG002223 from the National Human Genome Research Institute at the National Institutes of Health (NIH), for providing valuable genomic database information. We thank the Caenorhabditis elegans Genetics Center, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440), and the National Bioresource Project for the Nematode, Tokyo, Japan, for strains.

Publisher Copyright:
© 2018, ADMC Associazione Differenziamento e Morte Cellulare.


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