Abstract
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.
Highlights
The core programmed cell death pathway is highly regulated to maintain normal developmental and homeostatic processes
We demonstrate that the CDGSH iron sulfur domain (CISD) family members play a pro-survival role in the process of apoptosis and that they function through the BCL-2 gene encoding the apoptotic regulator (Bcl-2) family CED-9 and BH3 domain CED-13 but not through EGL-1
We show that the CISD-3 proteins in C. elegans have overlapping functions with CISD-1
Summary
The core programmed cell death pathway is highly regulated to maintain normal developmental and homeostatic processes. The displacement of NAF-1 from Bcl-2 binding occurs via the Endoplasmic Reticulum (ER) localized BH3-only protein Bik [1]. These results led to the hypothesis that the Bcl-2:NAF-1 complex at the ER plays a key role in regulating apoptosis and autophagy in mammalian cells [2,3,4].
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