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 beta-Amyloid precursor protein (beta APP) and Notch. beta APP is cleaved within its transmembrane domain by an aspartyl protease activity termed gamma-secretase, which may be identical with PS1 and PS2. Notch also undergoes a PS-dependent intramembraneous proteolysis. A similar gamma-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 gamma-secretase activity and whether inhibition of gamma-secretase activity would affect the UPR. Endoproteolysis of ATF6 was observed in the presence of the highly potent gamma-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 beta APP and Notch. Our results therefore demonstrate that ATF6 is not a substrate for PS mediated gamma-secretase-like endoproteolysis. This finding indicates that gamma-secretase inhibitors, which are currently developed as therapeutic agents to lower the A beta burden in brains of AD patients, do not interfere with the UPR response.
Steiner
H
H
Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Adolf-Butenandt-Institute, Ludwig-Maximilians-University, 80036 Munich, Germany.
Winkler
E
E
Shearman
M S
MS
Prywes
R
R
Haass
C
C
D051702:Activating Transcription Factor 6; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004151:Dipeptides / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D016296:Mutagenesis / Q000502:physiology; D058225:Plaque, Amyloid / Q000378:metabolism; D053764:Presenilin-1; D053766:Presenilin-2; D011480:Protease Inhibitors / Q000494:pharmacology; D051880:Receptors, Notch; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D016564:Amyloid beta-Protein Precursor; D002219:Carbamates; D004268:DNA-Binding Proteins; D004151:Dipeptides; C410009:L 685458; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D011480:Protease Inhibitors; D051880:Receptors, Notch; D014157:Transcription Factors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human