RCAN1 increases Aβ generation by promoting N-glycosylation via oligosaccharyltransferase.
Glycosylation is one of the major post-translational modifications, required for proper folding and functions of glycoproteins. N-glycosylation in ER is mediated by oligosaccharyltransferase (OST), an enzyme complex transferring preassembled oligosaccharide to asparagine residues of nascent polypeptide chain. Our study here indicates that regulator of calcineurin 1 (RCAN1) can enhance N-glycosylation in ER, therefore elevates the activities of β- and γ-secretase and markedly increases Aβ production. We found that RCAN1 stabilizes OST by interacting with OST component ribophorinI (RPN I). RCAN1 enhanced glycosylation of membrane proteins and glycosylation sequon GNSTVT, but has no effect on transferrin whose glycosylation was only affected by OST catalytic subunit STT3A, suggesting the effect of RCAN1 is associated with RPN I in facilitating substrate delivery. Our previous studies have shown that RCAN1 was increased in AD brains and RCAN1 overexpression induced neuronal apoptosis. Here our study showed that RCAN1 further contributes to AD pathogenesis by increasing N-glycosylation and Aβ production.
Tan
T
Wang
Heng
H
Liu
Yun
Y
Wang
Changqing
C
Liu
Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan, Shandong, 250012, P. R. China. xiulians@gmail.com.
Xiulian
X
Sun
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D004268:DNA-Binding Proteins; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006031:Glycosylation; D057809:HEK293 Cells; D006367:HeLa Cells; D006602:Hexosyltransferases / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D014168:Transferrin / Q000378:metabolism
D016229:Amyloid beta-Peptides; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009124:Muscle Proteins; C108612:RCAN1 protein, human; D014168:Transferrin; C413604:nicastrin protein; C034241:ribophorin; D006602:Hexosyltransferases; C025620:dolichyl-diphosphooligosaccharide - protein glycotransferase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human