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.