Ceramide biogenesis is required for radiation-induced apoptosis in the germ line of C. elegans.
Ceramide engagement in apoptotic pathways has been a topic of controversy. To address this controversy, we tested loss-of-function (lf) mutants of conserved genes of sphingolipid metabolism in Caenorhabditis elegans. Although somatic (developmental) apoptosis was unaffected, ionizing radiation-induced apoptosis of germ cells was obliterated upon inactivation of ceramide synthase and restored upon microinjection of long-chain natural ceramide. Radiation-induced increase in the concentration of ceramide localized to mitochondria and was required for BH3-domain protein EGL-1-mediated displacement of CED-4 (an APAF-1-like protein) from the CED-9 (a Bcl-2 family member)/CED-4 complex, an obligate step in activation of the CED-3 caspase. These studies define CEP-1 (the worm homolog of the tumor suppressor p53)-mediated accumulation of EGL-1 and ceramide synthase-mediated generation of ceramide through parallel pathways that integrate at mitochondrial membranes to regulate stress-induced apoptosis.
Deng
Xinzhu
X
Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY 10021, USA.
Yin
Xianglei
X
Allan
Richard
R
Lu
Diane D
DD
Maurer
Carine W
CW
Haimovitz-Friedman
Adriana
A
Fuks
Zvi
Z
Shaham
Shai
S
Kolesnick
Richard
R
D000818:Animals; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002518:Ceramides / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D017238:Genes, Helminth; D005854:Germ Cells / Q000166:cytology* / Q000378:metabolism / Q000528:radiation effects; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D009154:Mutation; D009685:Nuclear Envelope / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011839:Radiation, Ionizing; D012097:Repressor Proteins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C438244:CEP-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D002135:Calcium-Binding Proteins; C089224:Ced-4 protein, C elegans; C087233:Ced-9 protein, C elegans; D002518:Ceramides; C112486:EGL-1 protein, C elegans; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; C516680:ABL-1 protein, C elegans; D016315:Proto-Oncogene Proteins c-abl