Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 291, Issue 42, Pages 21903-21912Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.753582
Keywords
amyloid precursor protein (APP); amyloid (A); endoplasmic reticulum (ER); lysosome; rhomboid protease; APLP1; APLP2; APP fragments
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Funding
- Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN-2015-04645]
- Canada Foundation of Innovation Leaders Opportunity Fund Grant [32565]
- Alzheimer Society of Canada Young Investigator Award [PT-58872]
- Fonds d'innovation Pfizer-Fonds de recherche Sante Quebec (FRQS) sur la maladie d'Alzheimer et les maladies apparentees [31288]
- McGill University
- McGill Faculty of Medicine
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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 (A) 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 A 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.
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