PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1

Wen jie Luo, Hong Wang, Hongqiao Li, Benny S. Kim, Sanjiv Shah, Hahn Jun Lee, Gopal Thinakaran, Tae Wan Kim, Gang Yu, Huaxi Xu

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198 Scopus citations

Abstract

Presenilin (PS, PS1/PS2) complexes are known to be responsible for the intramembranous γ-secretase cleavage of the β-amyloid precursor protein and signaling receptor Notch. PS holoprotein undergoes endoproteolysis by an unknown enzymatic activity to generate NH2- and COOH-terminal fragments, a process that is required for the formation of the active and stable PS/-γ-secretase complex. Biochemical and genetic studies have recently identified nicastrin, APH-1, and PEN-2 as essential cofactors that physically interact with PS1 and are necessary for the γ-secretase activity. However, their precise function in regulating the PS complex and γ-secretase activity remains unknown. Here, we demonstrate that endogenous PEN-2 preferentially interacts with PS1 holoprotein. Down-regulation of PEN-2 expression by small interfering RNA (siRNA) abolishes the endoproteolysis of PS1, whereas overexpression of PEN-2 promotes the production of PS1 fragments, indicating a critical role for PEN-2 in PS1 endoproteolysis. Interestingly, accumulation of full-length PS1 resulting from down-regulation of PEN-2 is alleviated by additional siRNA down-regulation of APH-1. Furthermore, overexpression of APH-1 facilitates PEN-2-mediated PS1 proteolysis, resulting in a significant increase in PS1 fragments. Our data reveal a direct role of PEN-2 in proteolytic cleavage of PS1 and a regulatory function of APH-1, in coordination with PEN-2, in the biogenesis of the PS1 complex.

Original languageEnglish (US)
Pages (from-to)7850-7854
Number of pages5
JournalJournal of Biological Chemistry
Volume278
Issue number10
DOIs
StatePublished - Mar 7 2003

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Luo, W. J., Wang, H., Li, H., Kim, B. S., Shah, S., Lee, H. J., Thinakaran, G., Kim, T. W., Yu, G., & Xu, H. (2003). PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1. Journal of Biological Chemistry, 278(10), 7850-7854. https://doi.org/10.1074/jbc.C200648200