Eta-secretase-like processing of the amyloid precursor protein (APP) by the rhomboid protease RHBDL4

作者：Ylauna Christine Mégane Penalva, Sandra Paschkowsky, Sherilyn Junelle Recinto, Anthony Duchesne, Thomas H. Hammond, Pascal Spiegler, Gregor Jansen, Clémence Levet, François Charron, Matthew Freeman, R. Anne McKinney, Jean‐François Trempe, Lisa Marie Munter · 发表于：Journal of Biological Chemistry · 年份：2024 · DOI：10.1016/j.jbc.2024.107541 · 被引用次数：9 · 研究领域：Alzheimer's disease research and treatments、Bioinformatics and Genomic Networks、Protein Structure and Dynamics

The amyloid precursor protein (APP) is a key protein in Alzheimer's disease synthesized in the endoplasmic reticulum (ER) and translocated to the plasma membrane where it undergoes proteolytic cleavages by several proteases. Conversely, to other known proteases, we previously elucidated rhomboid protease RHBDL4 as a novel APP processing enzyme where several cleavages likely occur already in the ER. Interestingly, the pattern of RHBDL4-derived large APP C-terminal fragments resembles those generated by the η-secretase or MT5-MMP, which was described to generate so-called Aη fragments. The similarity in large APP C-terminal fragments between both proteases raised the question of whether RHBDL4 may contribute to η-secretase activity and Aη-like fragments. Here, we identified two cleavage sites of RHBDL4 in APP by mass spectrometry, which, intriguingly, lie in close proximity to the MT5-MMP cleavage sites. Indeed, we observed that RHBDL4 generates Aη-like fragments in vitro without contributions of α-, β-, or γ-secretases. Such Aη-like fragments are likely generated in the ER since RHBDL4-derived APP-C-terminal fragments do not reach the cell surface. Inherited, familial APP mutations appear to not affect this processing pathway. In RHBDL4 knockout mice, we observed increased cerebral full-length APP in comparison to wild type (WT) in support of RHBDL4 being a physiologically relevant protease for APP. Furthermore, we found secreted Aη fragments in dissociated mixed cortical cult...