MEMBRANE TRANSPORT STRUCTURE FUNCTION AND BIOGENESIS
PEN-2 and APH-1 Coordinately Regulate Proteolytic Processing of Presenilin 1*

https://doi.org/10.1074/jbc.C200648200Get rights and content
Under a Creative Commons license
open access

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.

Cited by (0)

Published, JBC Papers in Press, January 8, 2003, DOI 10.1074/jbc.C200648200

*

This work was supported by the National Institutes of Health Grant AG09464, by the Ellison Medical Foundation, and by the Alzheimer's Association.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

Both authors contributed equally to this work.