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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology*
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Atractyloside / pharmacology
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Bongkrekic Acid / pharmacology
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Caenorhabditis elegans / cytology*
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Caenorhabditis elegans / drug effects
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Caenorhabditis elegans / physiology*
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Caenorhabditis elegans Proteins / antagonists & inhibitors
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Caenorhabditis elegans Proteins / genetics
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Caenorhabditis elegans Proteins / physiology*
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / physiology
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Caspases / genetics
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Caspases / physiology
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Cell Line
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Gene Deletion
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Gene Expression
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Genes, Helminth
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Germ Cells / cytology
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Germ Cells / metabolism
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Humans
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Mitochondria / metabolism
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Mitochondrial ADP, ATP Translocases / antagonists & inhibitors
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Mitochondrial ADP, ATP Translocases / genetics
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Mitochondrial ADP, ATP Translocases / physiology*
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Multiprotein Complexes
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / physiology
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RNA Interference
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Repressor Proteins / genetics
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Repressor Proteins / physiology
Substances
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Caenorhabditis elegans Proteins
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Calcium-Binding Proteins
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Ced-4 protein, C elegans
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Ced-9 protein, C elegans
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EGL-1 protein, C elegans
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Multiprotein Complexes
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Proto-Oncogene Proteins c-bcl-2
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Repressor Proteins
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Bongkrekic Acid
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Atractyloside
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Mitochondrial ADP, ATP Translocases
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Caspases
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ced-3 protein, C elegans