title: Alternative Processing of the Amyloid Precursor Protein Family by Rhomboid Protease RHBDL4.
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.
authors: From the Department of Pharmacology and Therapeutics and.
authors: Sandra
authors: S
authors: Paschkowsky
authors: From the Department of Pharmacology and Therapeutics and.
authors: Mehdi
authors: M
authors: Hamzé
authors: From the Department of Pharmacology and Therapeutics and Integrated Program in Neuroscience, McGill University, Montreal, Quebec H3G 0B1, Canada.
authors: Felix
authors: F
authors: Oestereich
authors: From the Department of Pharmacology and Therapeutics and lisa.munter@mcgill.ca.
authors: Lisa Marie
authors: LM
authors: Munter
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D000072417:Protein Domains; D011499:Protein Processing, Post-Translational
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C466104:RHBDL3 protein, human
keywords: APLP1; APLP2; APP fragments; amyloid precursor protein (APP); amyloid β (Aβ); endoplasmic reticulum (ER); lysosome; rhomboid protease