Generation of anti-apoptotic presenilin-2 polypeptides by alternative transcription, proteolysis, and caspase-3 cleavage

PS2, the chromosome 1 familial Alzheimer's disease gent, has been shown to be involved in programmed cell death by three complementary experimental approaches. Reduction of PS2 protein levels by antisense RNA protects from apoptosis, whereas overexpression of an Alzheimer's PS2 mutant increases cell death induced by several stimuli. In addition, ALG-3, a truncated PS2 cDNA, encodes an artificial COOH-terminal PS2 segment that dominantly inhibits apoptosis. Here we describe a physiological COOH-terminal PS2 polypeptide (PS2s, Met²⁹⁸-Ile⁴⁴⁸) generated by both an alternative PS2 transcript and proteolytic cleavage. We find that PS2s protects transfected cells from Fas- and tumor necrosis factor α (TNFα)-induced apoptosis. Furthermore, a similar anti-apoptotic COOH-terminal PS2 polypeptide (PS2Ccas) is generated by caspase-3 cleavage at Asp³²⁹. These results suggest that caspase-3 not only activates pro-apoptotic substrates but also generates a negative feedback signal in which PS2Ccas antagonizes the progression of cell death. Thus, whereas PS2 is required for apoptosis, PS2s and PS2Ccas oppose this process, and the balance between PS2 and these COOH-terminal fragments may dictate the cell fate.