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Published online February 26, 2007
doi:10.1083/jcb.200609180
The Journal of Cell Biology, Vol. 176, No. 5, 629-640
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Spasic et al.
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Article

 Rer1p competes with APH-1 for binding to nicastrin and regulates {gamma}-secretase complex assembly in the early secretory pathway

Dragana Spasic1, Tim Raemaekers1, Katleen Dillen1, Ilse Declerck1, Veerle Baert1, Lutgarde Serneels2, Joachim Füllekrug3, and Wim Annaert1

1 Laboratory for Membrane Trafficking and 2 Neuronal Cell Biology and Gene Therapy, Center for Human Genetics, Katholieke Universiteit Leuven/Vlaams Instituut voor Biotechnologie, Gasthuisberg, Leuven, B-3000 Leuven, Belgium
3 Molecular Cell Biology Group, University of Heidelberg, 69120 Heidelberg, Germany

Correspondence to Wim Annaert: Willem.Annaert{at}med.kuleuven.be

The {gamma}-secretase complex, consisting of presenilin, nicastrin, presenilin enhancer-2 (PEN-2), and anterior pharynx defective-1 (APH-1) cleaves type I integral membrane proteins like amyloid precursor protein and Notch in a process of regulated intramembrane proteolysis. The regulatory mechanisms governing the multistep assembly of this "proteasome of the membrane" are unknown. We characterize a new interaction partner of nicastrin, the retrieval receptor Rer1p. Rer1p binds preferentially immature nicastrin via polar residues within its transmembrane domain that are also critical for interaction with APH-1. Absence of APH-1 substantially increased binding of nicastrin to Rer1p, demonstrating the competitive nature of these interactions. Moreover, Rer1p expression levels control the formation of {gamma}-secretase subcomplexes and, concomitantly, total cellular {gamma}-secretase activity. We identify Rer1p as a novel limiting factor that negatively regulates {gamma}-secretase complex assembly by competing with APH-1 during active recycling between the endoplasmic reticulum (ER) and Golgi. We conclude that total cellular {gamma}-secretase activity is restrained by a secondary ER control system that provides a potential therapeutic value.

T. Raemaekers and K. Dillen contributed equally to this paper.

Abbreviations used in this paper: Aß, amyloid ß; AICD, APP intracellular domain; APH, anterior pharynx defective; APP, amyloid precursor protein; BN-PAGE, blue native PAGE; COP, coat protein complex; CTF, C-terminal fragment; DTBP, dimethyl 3,3'-dithiobispropionimidate; endoH, endoglycosidase H; FL, full-length; IC, intermediate compartment; KO, knockout; MEF, mouse embryonic fibroblast; NCT, nicastrin; NTF, N-terminal fragment; PEN, PS enhancer; PS, presenilin; Rer1p, retrieval to ER 1 protein; TLN, telencephalin; TMD, transmembrane domain; WT, wild-type.


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