Endoproteolysis of the ER Stress Transducer ATF6 in the Presence of Functionally Inactive Presenilins

Presenilin (PS) proteins facilitate endoproteolysis of selected type I transmembrane proteins such as the Alzheimer's disease (AD) associated β-Amyloid precursor protein (βAPP) and Notch. βAPP is cleaved within its transmembrane domain by an aspartyl protease activity termed γ-secretase, which may be identical with PS1 and PS2. Notch also undergoes a PS-dependent intramembraneous proteolysis. A similar γ-secretase-like cleavage may also occur with IRE1 and ATF6, two signaling molecules of the unfolded protein response (UPR) that may require PSs for their activation. Here, we have analyzed whether ATF6 cleavage requires a PS-dependent γ-secretase activity and whether inhibition of γ-secretase activity would affect the UPR. Endoproteolysis of ATF6 was observed in the presence of the highly potent γ-secretase inhibitor L-685,458. ATF6 processing also occurred in the presence of functionally inactive dominant negative mutants of PS1 (PS1 D385N) and PS2 (PS2 D366A) that do not support endoproteolysis of βAPP and Notch. Our results therefore demonstrate that ATF6 is not a substrate for PS mediated γ-secretase-like endoproteolysis. This finding indicates that γ-secretase inhibitors, which are currently developed as therapeutic agents to lower the Aβ burden in brains of AD patients, do not interfere with the UPR response.