Presenilins and γ-secretase inhibitors affect intracellular trafficking and cell surface localization of the γ-secretase complex components Journal Article
| Authors: | Wang, H.; Luo, W. J.; Zhang, Y. W.; Li, Y. M.; Thinakaran, G.; Greengard, P.; Xu, H. |
| Article Title: | Presenilins and γ-secretase inhibitors affect intracellular trafficking and cell surface localization of the γ-secretase complex components |
| Abstract: | The intramembranous cleavage of Alzheimer β-amyloid precursor protein and the signaling receptor Notch is mediated by the presenilin (PS, PS1/PS2)-γ-secretase complex, the components of which also include nicastrin, APH-1, and PEN-2. In addition to its essential role in γ-secretase activity, we and others have reported that PS1 plays a role in intracellular trafficking of select membrane proteins including nicastrin. Here we examined the fate of PEN-2 in the absence of PS expression or γ-secretase activity. We found that PEN-2 is retained in the endoplasmic reticulum and has a much shorter half-life in PS-deficient cells than in wild type cells, suggesting that PSs are required for maintaining the stability and proper subcellular trafficking of PEN-2. However, the function of PS in PEN-2 trafficking is distinct from its contribution to γ-secretase activity because inhibition of γ-secretase activity by -γ-secretase inhibitors did not affect the PEN-2 level or its egress from the endoplasmic reticulum. Instead, membrane-permeable γ-secretase inhibitors, but not a membrane-impermeable derivative, markedly increased the cell surface levels of PS1 and PEN-2 without affecting that of nicastrin. In support of its role in PEN-2 trafficking, PS1 was also required for the γ-secretase inhibitor-induced plasma membrane accumulation of PEN-2. We further showed that γ-secretase inhibitors specifically accelerated the Golgi to the cell surface transport of PS1 and PEN-2. Taken together, we demonstrate an essential role for PSs in intracellular trafficking of the γ-secretase components, and that selective γ-secretase inhibitors differentially affect the trafficking of the γ-secretase components, which may contribute to an inactivation of γ-secretase. |
| Keywords: | controlled study; protein expression; unclassified drug; nonhuman; protein localization; proteins; protein analysis; animal cell; mouse; animals; mice; enzyme inhibition; protein stability; membrane proteins; notch receptor; intracellular transport; enzyme activity; cell line, tumor; wild type; time factors; animalia; blotting, western; endoplasmic reticulum; regulatory mechanism; enzyme inhibitors; membrane glycoproteins; enzyme inactivation; membrane protein; cell membrane; protein transport; cytoplasm; inhibition kinetics; arf protein; enzyme specificity; signal processing; subcellular fractions; alzheimer disease; biological transport; membrane permeability; membrane binding; amyloid precursor protein; gamma secretase inhibitor; nicastrin; amyloid precursor protein secretases; gamma secretase; presenilin 1; presenilin 2; biotinylation; presenilin-1; endopeptidases; golgi complex; cell surface; protein defect; membranes; golgi apparatus; rab protein; aspartic endopeptidases; protein pen2; precipitin tests; priority journal; article; plasma applications; endoplasmic recticulum; signal receptors; anterior pharynx defective 1 protein; gamma adaptin |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 279 |
| Issue: | 39 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2004-09-24 |
| Start Page: | 40560 |
| End Page: | 40566 |
| Language: | English |
| DOI: | 10.1074/jbc.M404345200 |
| PROVIDER: | scopus |
| PUBMED: | 15247291 |
| DOI/URL: | |
| Notes: | J. Biol. Chem. -- Cited By (since 1996):36 -- Export Date: 16 June 2014 -- CODEN: JBCHA -- Source: Scopus |
