Sumoylation of amyloid precursor protein negatively regulates Abeta aggregate levels.
The proteolytic processing of amyloid precursor protein (APP) to produce Abeta peptides is thought to play an important role in the mechanism of Alzheimer's disease. Here, we show that lysines 587 and 595 of APP, which are immediately adjacent to the site of beta-secretase cleavage, are covalently modified by SUMO proteins in vivo. Sumoylation of these lysine residues is associated with decreased levels of Abeta aggregates. Further, overexpression of the SUMO E2 enzyme ubc9 along with SUMO-1 results in decreased levels of Abeta aggregates in cells transfected with the familial Alzheimer's disease-associated V642F mutant APP, indicating the potential of up-regulating activity of the cellular sumoylation machinery as an approach against Alzheimer's disease. The results also provide the first demonstration that the SUMO E2 enzyme (ubc9) is present within the endoplasmic reticulum, indicating how APP, and perhaps other proteins that enter this compartment, can be sumoylated.
Zhang
Yu-Qian
YQ
Department of Molecular and Cellular Biochemistry, University of Kentucky, 741 S. Limestone Street, Lexington, KY 40536, USA.
Sarge
Kevin D
KD
D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000201:enzymology; D006367:HeLa Cells; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D014162:Transfection; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism*; D000098843:Ubiquitin-Conjugating Enzyme UBC9
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C117909:SUMO2 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D044763:Ubiquitin-Conjugating Enzymes; D053829:Amyloid Precursor Protein Secretases; D000098843:Ubiquitin-Conjugating Enzyme UBC9; D008239:Lysine