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dc.contributor.authorZhang, Y. W.zh_CN
dc.contributor.authorLuo, W. J.zh_CN
dc.contributor.authorWang, H.zh_CN
dc.contributor.authorLin, P.zh_CN
dc.contributor.authorVetrivel, K. S.zh_CN
dc.contributor.authorLiao, F.zh_CN
dc.contributor.authorLi, F.zh_CN
dc.contributor.authorWong, P. C.zh_CN
dc.contributor.authorFarquhar, M. G.zh_CN
dc.contributor.authorThinakaran, G.zh_CN
dc.contributor.authorXu, H.zh_CN
dc.contributor.author张云武zh_CN
dc.date.accessioned2013-12-12T02:25:43Z
dc.date.available2013-12-12T02:25:43Z
dc.date.issued2005zh_CN
dc.identifier.citationJournal of Biological Chemistry,280(17):17020-17026zh_CN
dc.identifier.issn0021-9258zh_CN
dc.identifier.urihttps://dspace.xmu.edu.cn/handle/2288/66015
dc.description.abstractgamma-Secretase, which is responsible for the intramembranous cleavage of Alzheimer beta-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/gamma-secretase components. However, the precise functions of the other components remain elusive. Here, we investigated the functions of Nct within the PS1/gamma-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 gamma-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 center dot 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/ gamma-secretase complex but not in maintaining the association of PEN-2, APH-1, and full-length PS1.zh_CN
dc.language.isoen_USzh_CN
dc.subjectAMYLOID PRECURSOR PROTEINzh_CN
dc.subjectGAMMA-SECRETASEzh_CN
dc.subjectCELL-SURFACEzh_CN
dc.subjectINTRACELLULAR TRAFFICKINGzh_CN
dc.subjectINTRAMEMBRANE PROTEOLYSISzh_CN
dc.subjectENDOPLASMIC-RETICULUMzh_CN
dc.subjectCOMPLEX COMPONENTSzh_CN
dc.subjectALZHEIMERS-DISEASEzh_CN
dc.subjectAPH-1 INTERACTSzh_CN
dc.subjectBETA-APPzh_CN
dc.titleNicastrin is critical for stability and trafficking but not association of other presenilin/gamma-secretase componentszh_CN
dc.typeArticlezh_CN


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