Dilysine retrieval signal-containing p24 proteins collaborate in inhibiting γ-cleavage of amyloid precursor protein.

γ-Secretase mediates intramembranous γ-cleavage and ε-cleavage of β-amyloid precursor protein (APP) to liberate β-amyloid peptide (Aβ) and APP intracellular domain respectively from the membrane. Although the regulatory mechanism of γ-secretase cleavage remains unresolved, a member of the p24 cargo protein family, named p24δ(1) or TMP21, has been identified as an activity-modulating component. The p24 family proteins are divided into four subfamilies (p24α, β, δ and γ). In contrast to p24δ(1), p24β(1) has reportedly no effect on γ-cleavage. In this study, we determined whether p24α(2), p24γ(3) or p24γ(4) modulates APP processing. Knockdown of cellular p24α(2) induced a significant increase in Aβ generation but not in APP intracellular domain production in cell-based and cell-free assays, whereas p24α(2) over-expression suppressed Aβ secretion. By contrast, Aβ secretion was not altered by p24γ(3) or p24γ(4) knockdown. Endogenous p24α(2) co-immunoprecipitated with core components of the γ-secretase complex, and the anti-p24α(2) immunoprecipitate exhibited γ-secretase activity. Mutational disruption of the conserved dilysine ER-retrieval motifs of p24α(2) and p24δ(1) perturbed inhibition of γ-cleavage. Simultaneous knockdown, or co-over-expression, of these proteins had no additive or synergistic effect on Aβ generation. Our findings suggest that dilysine ER-retrieval signal-containing p24 proteins, p24α(2) and p24δ(1), bind with γ-secretase complexes and collaborate in attenuating γ-cleavage of APP.

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