ATF4 regulates gamma-secretase activity during amino acid imbalance.
Accumulation of amyloid-beta (Abeta), which is generated from amyloid precursor protein by gamma-secretase, in cerebral cortex is common and critical incident in Alzheimer disease. Specifically, presenilin is an essential for gamma-secretase activity. However, the regulation of presenilin expression, affecting gamma-secretase activity, remains obscure. We investigated mechanism controlling the expression of presenilin-1 (PS1) and gamma-secretase activity. We showed that PS1 is induced by activating transcription factor 4 (ATF4), regulated by GCN2 eukaryotic initiation factor 2alpha (eIF2alpha) kinase. A chromatin immunoprecipitation analysis and an electrophoretic mobility shift assay demonstrated that ATF4 binds to the regulatory region of human PS1 gene. Through knockdown analysis, we observed that the secretion of Abeta (1-42) and induction of gamma-secretase cofactors are controlled by ATF4. These data indicate that ATF4 is critical for gamma-secretase activity, by which ATF4 mRNA is preferentially translated in response to eIF2alpha phosphorylation.
Mitsuda
Teruhiko
T
Department of Neurobiology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
Hayakawa
Yoshika
Y
Itoh
Masanori
M
Ohta
Kazunori
K
Nakagawa
Toshiyuki
T
D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000601:Amino Acids, Essential / Q000172:deficiency*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D005246:Feedback; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053764:Presenilin-1 / Q000378:metabolism*
D000601:Amino Acids, Essential; C081452:Atf4 protein, mouse; D053764:Presenilin-1; D051701:Activating Transcription Factor 4; D053829:Amyloid Precursor Protein Secretases