FAD-linked presenilin-1 mutants impede translation regulation under ER stress.
FAD mutations in presenilin-1 (PS1) cause attenuation of the induction of the endoplasmic reticulum (ER)-resident chaperone GRP78/BiP under ER stress, due to disturbed function of IRE1, the sensor for accumulation of unfolded protein in the ER lumen. PERK, an ER-resident transmembrane protein kinase, is also a sensor for the unfolded protein response (UPR), causing phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) to inhibit translation initiation. Here, we report that the FAD mutant PS1 disturbs the UPR by attenuating both the activation of PERK and the phosphorylation of eIF2alpha. Consistent with the results of a disturbed UPR, inhibition of protein synthesis under ER stress was impaired in cells expressing PS1 mutants. These results suggest that mutant PS1 impedes general translational attenuation regulated by PERK and eIF2alpha, resulting in an increased load of newly synthesized proteins into the ER and subsequently increasing vulnerability to ER stress.
Yasuda
Yuka
Y
Division of Psychiatry and Behavioral Proteomics, Department of Post-Genomics and Diseases, Course of Advanced Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Siuta, Osaka, Japan. kudo@psy.med.osaka-u.ac.jp
Kudo
Takashi
T
Katayama
Taiichi
T
Imaizumi
Kazunori
K
Yatera
Misako
M
Okochi
Masayasu
M
Yamamori
Hidenaga
H
Matsumoto
Naohiko
N
Kida
Takayuki
T
Fukumori
Akio
A
Okumura
Masayo
M
Tohyama
Masaya
M
Takeda
Masatoshi
M
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D053764:Presenilin-1; D014176:Protein Biosynthesis; D015398:Signal Transduction / Q000502:physiology; D019892:eIF-2 Kinase / Q000378:metabolism
D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D008565:Membrane Proteins; D053764:Presenilin-1; D019892:eIF-2 Kinase; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C508853:PSEN1 protein, human