ArticleThe Journal of biological chemistry2016
Alternative Processing of the Amyloid Precursor Protein Family by Rhomboid Protease RHBDL4.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 58 citations in OpenAlex.
- Rhomboid protease RHBDL2 is a calcium-activated suppressor of EGFR signalling in keratinocytes.Cellular and molecular life sciences : CMLS · 2026Article
- Targeting the Membrane-Embedded Rhomboid Protease GlpG: A Multimodal Strategy for Inhibitor Discovery and Mechanistic Insight.Angewandte Chemie (International ed. in English) · 2026Article
- Rhomboid protease Rhbdl2 regulates macrophage recruitment and wound regeneration in zebrafish.bioRxiv : the preprint server for biology · 2026Article
- Advances in Research on Endoplasmic Reticulum-Associated Degradation Mechanisms in Neurodegenerative Diseases.Cellular and molecular neurobiology · 2026Review
- K48-ubiquitin-dependent proteases cut-up post-ER proteins.Nature communications · 2026Article
- The role of ER-associated degradation and ER-phagy in health and disease.Signal transduction and targeted therapy · 2026Review
- Rhomboid protease GlpG regulates type 1 pili quality control and virulence in pathogenic E. coli.Nature communications · 2025Article
- Holding Out for a Model: Rhomboid Superfamily in Vertebrate Development and Disease.Journal of cellular physiology · 2025Review
- Multi-omics machine learning classifier and blood transcriptomic signature of Parkinson's disease.Research square · 2025Article
- Loss of the APP regulator RHBDL4 preserves memory in an Alzheimer's disease mouse model.Cell death & disease · 2025Article
- Rhomboid proteases: key players at the cell surface within haloarchaea.Frontiers in microbiology · 2025Article
- AnbioRxiv : the preprint server for biology · 2024Article
- Activity-Based Protein Profiling of RHBDL4 Reveals Proteolysis of the Enzyme and a Distinct Inhibitor Profile.ACS chemical biology · 2024Article
- Transcriptional pathobiology and multi-omics predictors for Parkinson's disease.bioRxiv : the preprint server for biology · 2024Article
- RHBDL4-triggered downregulation of COPII adaptor protein TMED7 suppresses TLR4-mediated inflammatory signaling.Nature communications · 2024Article
- Cleavage of the pseudoprotease iRhom2 by the signal peptidase complex reveals an ER-to-nucleus signaling pathway.Molecular cell · 2024Article
- The opening dynamics of the lateral gate regulates the activity of rhomboid proteases.Science advances · 2023Article
- The Role of the Rhomboid Superfamily in ER Protein Quality Control: From Mechanisms and Functions to Diseases.Cold Spring Harbor perspectives in biology · 2023Review
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Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.