Disruption of ceramide synthesis by CerS2 down-regulation leads to autophagy and the unfolded protein response

Disruption of ceramide synthesis by CerS2 down-regulation leads to autophagy and the unfolded protein response: "Ceramide metabolism has come under recent scrutiny because of its role in cellular stress responses. Ceramide synthase 2 (CerS2) is one of the six mammalian isoforms of ceramide synthase, and it is responsible for the synthesis of very-long chain (VLC) ceramides, e.g. C₂₄, _C24:1. To study the role of CerS2 in ceramide metabolism and cellular homeostasis, we down-regulated CerS2 using siRNA and examined several aspects of sphingolipid metabolism and cell stress responses. CerS2 down-regulation had a broad effect on ceramide homeostasis, not just on VLC ceramides. Surprisingly, CerS2 down-regulation resulted in significantly increased long-chain (LC) ceramides, e.g. C₁₄, C₁₆, and our data suggested that the increase was due to ceramide synthase-independent mechanism. CerS2-down-regulation-induced LC ceramide accumulation resulted in growth arrest that was not accompanied by apoptotic cell death. Instead, cells remained viable, showing induction of autophagy, and activation of PERK and IRE pathways (the latter indicating activation of the unfolded protein response (UPR))."