...we showed that early after apoptosis induction specific forms of ceramide (predominantly C16 ceramide) are formed in a way that was independent from caspases...

The role of ceramide in the induction of apoptosis is a hot item in the apoptosis research field. This study describes specificity in the formation of ceramide species via the de novo pathway of sphingolipid biosynthesis in response to activation induced B-cell death. Moreover, we directly link the formation of specific ceramide species (C16-ceramide) to the mitochondrial induction-phase of apoptosis.

In this study, we use a new method to semi-quantitatively analyze specific ceramide species by normal phase high performance liquid chromatography coupled to atmospheric pressure ionization mass spectrometry. Using this methodology was a strong point in our studies to demonstrate the differential kinetics of specific ceramide-species formation.

Coming from an immunotherapeutic research field I got increasingly interested in the basic mechanisms underlying immune cell death and survival. In this respect, sphingolipids appeared to be an intriguing class of biological response modifiers to study because of their reported involvement in both apoptosis and survival of immune cells. This prompted me to visit the lab of Prof. Yusuf Hannun to explore the involvement of sphingolipid metabolism in the regulation of immune homeostasis. This line of research is currently continued in my lab in The Netherlands.

Ceramide belongs to a family of lipids known as sphingolipids. Sphingolipids are structural components of the cell membranes and mediate in diverse cellular responses towards stress. In particular, formation of ceramide is involved in the induction of a genetically programmed form of cell death termed apoptosis. This form of cell death involves the activation of cell-destructive enzymes, caspases, and is crucial for maintaining homeostasis within the immune system. In our studies thus far (JBC, 276:13606 and JBC, 278: 14723), we have identified the biochemical route through which ceramide is formed in immune B-cells during the process of apoptosis. In addition, we showed that early after apoptosis induction specific forms of ceramide (predominantly C16- ceramide) are formed in a way that was independent from caspases. In contrast, later after apoptosis induction other ceramide species (predominantly C24) are formed in a way that required caspase activation. Moreover, we showed that the early formation of ceramide was involved in the activation of a non-caspase protease complex, known as the proteasome, leading to the degradation of an endogenous caspase inhibitor XIAP. Thus, we postulate that the early increase in C16 ceramide may result in caspase activation via proteasome-mediated degradation of XIAP, by which caspases become activated through which the secondarily formed C24 ceramide is regulated.