Presenilin-dependent gamma-secretase on plasma membrane and endosomes is functionally distinct.
The presenilin (PS)/gamma-secretase complex, which contains not only PS but also Aph-1, PEN-2, and nicastrin, mediates proteolysis of the transmembrane domain of beta-amyloid protein precursor (betaAPP). Intramembrane proteolysis occurs at the interface between the membrane and cytosol (epsilon-site) and near the middle of the transmembrane domain (gamma-site), generating the betaAPP intracellular domain (AICD) and Alzheimer disease-associated Abeta, respectively. Both cleavage sites exhibit some diversity. Changes in the precision of gamma-cleavage, which potentially results in secretion of pathogenic Abeta42, have been intensively studied, while those of epsilon-cleavage have not. Although a number of PS-associated factors have been identified, it is unclear whether any of them physiologically regulate the precision of cleavage by PS/gamma-secretase. Moreover, there is currently no clear evidence of whether PS/gamma-secretase function differs according to the subcellular site. Here, we show that endocytosis affects the precision of PS-dependent epsilon-cleavage in cell culture. Relative production of longer AICDepsilon49 increases on the plasma membrane, whereas that of shorter AICDepsilon51 increases on endosomes; however, this occurs without a concomitant major change in the precision of cleavage at gamma-sites. Moreover, very similar changes in the precision of epsilon-cleavage are induced by alteration of the pH. Our findings demonstrate that the precision of epsilon-cleavage by PS/gamma-secretase changes depending upon the conditions and the subcellular location. These results suggest that the precision of cleavage by the PS/gamma-secretase complex may be physiologically regulated by the subcellular location and conditions.
Fukumori
Akio
A
Division of Psychiatry and Behavioral Proteomics, Department of Post-Genomics and Diseases, Osaka University Graduate School of Medicine, Osaka, Japan.
Okochi
Masayasu
M
Tagami
Shinji
S
Jiang
Jingwei
J
Itoh
Naohiro
N
Nakayama
Taisuke
T
Yanagida
Kanta
K
Ishizuka-Katsura
Yoshiko
Y
Morihara
Takashi
T
Kamino
Kojin
K
Tanaka
Toshihisa
T
Kudo
Takashi
T
Tanii
Hisashi
H
Ikuta
Akiko
A
Haass
Christian
C
Takeda
Masatoshi
M
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D002462:Cell Membrane / Q000201:enzymology* / Q000378:metabolism; D002478:Cells, Cultured; D004705:Endocytosis; D010450:Endopeptidases / Q000378:metabolism*; D011992:Endosomes / Q000502:physiology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D053764:Presenilin-1
D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human