Abstract
The amyloid precursor protein (APP) is an ubiquitously expressed cell surface protein and a key molecule in the etiology of Alzheimer disease. Amyloidogenic processing of APP through secretases leads to the generation of toxic amyloid β (Aβ) peptides, which are regarded as the molecular cause of the disease. We report here an alternative processing pathway of APP through the mammalian intramembrane rhomboid protease RHBDL4. RHBDL4 efficiently cleaves APP inside the cell, thus bypassing APP from amyloidogenic processing, leading to reduced Aβ levels. RHBDL4 cleaves APP multiple times in the ectodomain, resulting in several N- and C-terminal fragments that are not further degraded by classical APP secretases. Knockdown of endogenous RHBDL4 results in decreased levels of C-terminal fragments derived from endogenous APP. Similarly, we found the APP family members APLP1 and APLP2 to be substrates of RHBDL4. We conclude that RHBDL4-mediated APP processing provides insight into APP and rhomboid physiology and qualifies for further investigations to elaborate its impact on Alzheimer disease pathology.
Highlights
The amyloid precursor protein (APP)2 is abundantly expressed throughout the human body and shows high levels in the brain, lung, and liver [1]
We propose that processing of APP by RHBDL4 is an alternative APP processing pathway, maybe functioning to regulate levels of APP presented at the cell surface, which may further our understanding of APP biology
Analysis of Novel RHBDL4-mediated APP Fragments— Because APP is processed by ␣-secretase, BACE1, and ␥-secretases, we investigated whether the RHBDL4-mediated cleavage
Summary
The amyloid precursor protein (APP) is abundantly expressed throughout the human body and shows high levels in the brain, lung, and liver [1]. Sequential cleavage of APP by BACE1 and ␥-secretase results in the generation of harmful amyloid  (A) peptides, which are proposed as the molecular cause of Alzheimer disease [12]. ␥-Secretase is an intramembrane protease and cleaves the APP transmembrane sequence at multiple sites, generating A peptides with predominantly 38, 40, and 42 amino acids, which are secreted [13]. Rhomboid proteases are evolutionarily conserved and found in all kingdoms of life, including archaea, prokaryotes, plants, and animals [15, 16] Such conservation suggests that they successfully withstood evolutionary pressure and carry out essential biological functions. Active rhomboid proteases directly recognize their substrates and do not require an initiating ectodomain shedding event, unlike ␥-secretase [27]. We show that the APP family members are efficient substrates for the rhomboid protease RHBDL4. We propose that processing of APP by RHBDL4 is an alternative APP processing pathway, maybe functioning to regulate levels of APP presented at the cell surface, which may further our understanding of APP biology
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