SERP1 is an assembly regulator of γ-secretase in metabolic stress conditions.

SERP1 is an assembly regulator of γ-secretase in metabolic stress conditions. Sci Signal. 2020 Mar 17;13(623): Authors: Jung S, Hyun J, Nah J, Han J, Kim SH, Park J, Oh Y, Gwon Y, Moon S, Jo DG, Jung YK Abstract The enzyme γ-secretase generates β-amyloid (Aβ) peptides by cleaving amyloid protein precursor (APP); the aggregation of these peptides is associated with Alzheimer's disease (AD). Despite the development of various γ-secretase regulators, their clinical use is limited by coincident disruption of other γ-secretase-regulated substrates, such as Notch. Using a genome-wide functional screen of γ-secretase activity in cells and a complementary DNA expression library, we found that SERP1 is a previously unknown γ-secretase activator that stimulates Aβ generation in cells experiencing endoplasmic reticulum (ER) stress, such as is seen with diabetes. SERP1 interacted with a subcomplex of γ-secretase (APH1A/NCT) through its carboxyl terminus to enhance the assembly and, consequently, the activity of the γ-secretase holoenzyme complex. In response to ER stress, SERP1 preferentially recruited APP rather than Notch into the γ-secretase complex and enhanced the subcellular localization of the complex into lipid rafts, increasing Aβ production. Moreover, SERP1 abundance, γ-secretase assembly, and Aβ production were increased both in cells exposed to high amounts of glucose and in diabetic AD model mice. Conversely, Aβ prod...
Source: Science Signaling - Category: Biomedical Science Authors: Tags: Sci Signal Source Type: research