Cathepsin D targeted by acid sphingomyelinase-derived ceramide

Ceramide has been recognized as a common intracellular second messenger for various cytokines, growth factors and other stimuli, such as CD95, chemoth erapeutic drugs and stress factors. To understand the role of ceramide duri ng apoptosis and other cellular responses, it is critically important to ch aracterize direct targets of ceramide action. In this paper, we show that c eramide specifically binds to and activates the endosomal acidic aspartate protease cathepsin D, Direct interaction of ceramide with cathepsin D resul ts in autocatalytic proteolysis of the 52 kDa pre-pro cathepsin D to form t he enzymatically active 48/32 kDa isoforms of cathepsin D. Acid sphingomyel inase (A-SMase)-deficient cells show decreased cathepsin D activity, which could be reconstituted by transfection with A-SMase cDNA, The results of ou r study identify cathepsin D as the first endosomal ceramide target that co localizes with and may mediate downstream signaling effects of A-SMase.