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Cathepsin D targeted by acid sphingomyelinase-derived ceramide.
M Heinrich1, M Wickel, W Schneider-Brachert
1Institute of Immunology, University of Kiel, Kiel, Germany.
The EMBO Journal
|October 3, 1999
Summary
Ceramide activates the endosomal protease cathepsin D, a key step in cellular signaling. This finding identifies cathepsin D as the first direct ceramide target involved in apoptosis and stress responses.
Area of Science:
- Cell Biology
- Biochemistry
- Molecular Signaling
Background:
- Ceramide acts as a crucial intracellular second messenger in response to various stimuli.
- Understanding ceramide's role in apoptosis and cellular responses requires identifying its direct molecular targets.
Purpose of the Study:
- To identify and characterize direct cellular targets of ceramide action.
- To elucidate the role of ceramide in mediating cellular responses like apoptosis.
Main Methods:
- Investigated the interaction between ceramide and the endosomal protease cathepsin D.
- Analyzed the effect of ceramide on the autocatalytic proteolysis of pre-pro cathepsin D.
- Utilized acid sphingomyelinase (A-SMase)-deficient cells and A-SMase cDNA transfection to assess cathepsin D activity.
Main Results:
- Ceramide specifically binds to and activates the endosomal acidic aspartate protease cathepsin D.
- Direct interaction triggers the autocatalytic conversion of pre-pro cathepsin D into active isoforms.
- A-SMase-deficient cells exhibit reduced cathepsin D activity, which is restored upon A-SMase reintroduction.
Conclusions:
- Cathepsin D is identified as the first endosomal ceramide target.
- Cathepsin D colocalizes with acid sphingomyelinase and may mediate its downstream signaling effects.
- This discovery provides a new mechanistic link between ceramide signaling and cellular responses.