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J. Biol. Chem., Vol. 280, Issue 17, 17020-17026, April 29, 2005

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Nicastrin Is Critical for Stability and Trafficking but Not Association of Other Presenilin/-Secretase Components^*

Yun-wu Zhang, Wen-jie Luo, Hong Wang, Ping Lin¶, Kulandaivelu S. Vetrivel||, Fang Liao, Feng Li, Philip C. Wong**, Marilyn G. Farquhar¶, Gopal Thinakaran||, and Huaxi Xu

From the Center for Neuroscience and Aging, The Burnham Institute, La Jolla, California 92037, Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021, ^¶Department of Cellular and Molecular Medicine and Pathology, University of California San Diego, La Jolla, California 92093, ^||Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Illinois 60637, and ^**Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

-Secretase, which is responsible for the intramembranous cleavage of Alzheimer -amyloid precursor protein and the signaling receptor Notch, is a multiprotein complex consisting of at least four components: presenilin (PS); nicastrin (Nct); APH-1 (anterior pharynx-defective-1); and presenilin enhancer-2 (PEN-2). Presenilin 1 (PS1) is known to be essential for the stability, interaction, and trafficking of the other PS1/-secretase components. However, the precise functions of the other components remain elusive. Here, we investigated the functions of Nct within the PS1/-secretase complex. We demonstrated that the loss of Nct expression in the embryonic fibroblast cells (Nct KO cells) results in dramatically decreased levels of APH-1, PEN-2, and PS1 fragments accompanied by a significant accumulation of full-length PS1. In the absence of Nct, PEN-2 and full-length PS1 are subjected to proteasome-mediated degradation, whereas the degradation of APH-1 is mediated by both proteasomal and lysosomal pathways. Unlike the case of wild type cells in which the -secretase complex mainly locates in the trans-Golgi network, the majority of residual PEN-2, APH-1, and the uncleaved full-length PS1 in Nct KO cells reside in the endoplasmic reticulum, which remain associated with each other in the absence of Nct. Interestingly, significant amounts of full-length PS1 and PEN-2, but not APH-1, are detected on the plasma membrane in Nct KO cells, suggesting the Nct-independent cell surface delivery of the PEN-2·PS1. Finally, the diminished PEN-2 protein level in Nct-deficient cells can be partially restored by overexpression of exogenous PS1, APH-1, or PEN-2 individually or collectively, indicating a dispensable role for Nct in controlling PEN-2 level. Taken together, our study demonstrates a critical role of Nct in the stability and proper intracellular trafficking of other components of the PS1/ -secretase complex but not in maintaining the association of PEN-2, APH-1, and full-length PS1.

Received for publication, August 18, 2004 , and in revised form, January 21, 2005.

^* This work was supported by National Institutes of Health Grants NS046673 (to H. X.), AG021173 (to H. X.), F32 AG024895-01A1 (to Y. Z.), F32 AG023432-01 (to W. L.), AG021495 (to G. T.), and by Alzheimer's Association (to H. X. and G. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 858-713-9946; Fax: 858-713-6273; E-mail: xuh{at}burnham.org.

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