Analysis of the role of Herp in the generation of amyloid β protein and in the ER stress

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Herp is an endoplasmic reticulum (ER)-stress-inducible membrane protein that has a ubiquitin-like domain (ULD). However, its biological function is not yet known. Previously, we reported that a high expression level of Herp in cells enhances the generation of amyloid β-protein (Aβ) and that Herp interacts with presenilin (PS). Aβ is generated from amyloid precursor protein (APP) by sequential proteolytic cleavages catalyzed by β- and γ-secretases. PS is processed to its stable form by endoproteolysis. The cellular level of processed PS is highly regulated, and excess unprocessed PS enters the ubiquitin/proteasome degradation pathway. Processed PS resides in a high-molecular-weight complex that includes three membrane proteins, namely, Nacastrin (NCT), APH-1 and PEN-2. Accumulating evidence shows that the PS complex is responsible for y-secretase activity. In this study, we addressed the role of Herp in the regulation of PS complex formation. We found that the expression of ULD-deleted Herp markedly inhibited the degradation of unprocessed PS or NCT that fails to be incorporated into the PS complex. We also found that the expression of ULD-deleted Herp decreased a degree of ubiqutination of PS and NCT, while the expression of wild-type Herp enhanced it, strongly suggesting that ULD of Herp is involved for the ubiquitination of PS and NCT. Thus, Herp is likely to play a role, through its ubiquitin-like domain, in the elimination of excess PS or PS cofactors which fail to reside in the PS complex, thereby regulating the intracellular level of the PS complex.