Adenine Nucleotide Translocator Cooperates with Core Cell Death Machinery To Promote Apoptosis in Caenorhabditis elegans

Abstract

In Caenorhabditis elegans, the central cell-killing process is essentially controlled by the interplay of four apoptotic factors: EGL-1/BH3-only protein, CED-9/Bcl2, CED-4/Apaf1, and CED-3/caspase. In cells destined to die, EGL-1 binds to CED-9 and results in the release of CED-4 from the mitochondrion-tethered CED-9-CED-4 complex to the perinucleus, which facilitates processing of the CED-3 caspase to cause apoptosis. However, whether additional factors exist to regulate the cell-killing process remains largely unknown. We have identified here WAN-1, the C. elegans ortholog of mammalian adenine nucleotide translocator, as an important cell death regulator. Genetic inactivation of wan-1 significantly suppressed both somatic and germ line cell deaths in C. elegans. Consistently, chemical inhibition of WAN-1 activity also caused strong reduction of germ line apoptosis. WAN-1 localizes to mitochondria and can form complex with both CED-4 and CED-9. Importantly, the cell death initiator EGL-1 can disrupt the interaction between CED-9 and WAN-1. In addition, overexpression of WAN-1 induced ectopic cell killing dependently on the core cell death pathway. These findings suggest that WAN-1 is involved in the central cell-killing process and cooperates with the core cell death machinery to promote programmed cell death in C. elegans.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

We thank the C. elegans Genetic Center (CGC) for providing worm deletion strains; Shanting Hao for help with mass spectrometric analysis, Yingfang Liu for structure modeling of WAN-1, and Xiaochen Wang and Xun Huang for helpful suggestions and critical reading of the manuscript.

This research was supported by grants 2007CB947201 and 2006CB504100 from the National Basic Research Program of China, grants 30771059 and 30871266 from the National Natural Science Foundation of China, grant 2006AA02Z147 from the 863 Program of China, and grant KSCX1-YW-R-70 from the Chinese Academy of Sciences. C.Y. is supported by the 100-Talents Program of the Chinese Academy of Sciences.