A role for presenilin 1 in regulating the delivery of amyloid precursor protein to the cell surface.
Presenilin 1 (PS1) and presenilin 2 play a critical role in the gamma-secretase processing of amyloid precursor protein (APP) and Notch1. Here, we investigate maturation and intracellular trafficking of APP and other membrane proteins in cells expressing an experimental PS1 deletion mutant (deltaM1,2). Stable expression of deltaM1,2 impairs gamma-secretase processing of Notch1 and delays Abeta secretion. Kinetic studies show enhanced O-glycosylation and sialylation of holo-APP and marked accumulation of APP COOH-terminal fragments (CTFs). Surface biotinylation, live staining, and trafficking studies show increased surface accumulation of holo-APP and CTFs in deltaM1,2 cells resulting from enhanced surface delivery of newly synthesized APP. Expression of a loss-of-function PS1 mutant (D385A) or incubation of cells with gamma-secretase inhibitors also increases surface levels of holo-APP and CTFs. In contrast to APP, glycosylation and surface accumulation of another type I membrane protein, nicastrin, are markedly reduced in deltaM1,2 cells. Finally, expression of deltaM1,2 results in the increased assembly and surface expression of nicotinic acetylcholine receptors, illustrating that PS1's influence on protein trafficking extends beyond APP and other type I membrane protein substrates of gamma-secretase. Collectively, our findings provide evidence that PS1 regulates the glycosylation and intracellular trafficking of APP and select membrane proteins.
Leem
Jae Yoon
JY
Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Illinois 60637, USA.
Saura
Carlos A
CA
Pietrzik
Claus
C
Christianson
John
J
Wanamaker
Christian
C
King
LaShaunda T
LT
Veselits
Margaret L
ML
Tomita
Taisuke
T
Gasparini
Laura
L
Iwatsubo
Takeshi
T
Xu
Huaxi
H
Green
William N
WN
Koo
Edward H
EH
Thinakaran
Gopal
G
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002478:Cells, Cultured; D010450:Endopeptidases / Q000378:metabolism; D017353:Gene Deletion; D015870:Gene Expression; D006031:Glycosylation; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1; D053766:Presenilin-2; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D053766:Presenilin-2; D011978:Receptors, Nicotinic; C100690:amyloid beta-protein p3, human; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human