| First Author | Penalva YCM | Year | 2024 |
| Journal | J Biol Chem | Volume | 300 |
| Issue | 8 | Pages | 107541 |
| PubMed ID | 38992438 | Mgi Jnum | J:359044 |
| Mgi Id | MGI:7713705 | Doi | 10.1016/j.jbc.2024.107541 |
| Citation | Penalva YCM, et al. (2024) Eta-secretase-like processing of the amyloid precursor protein (APP) by the rhomboid protease RHBDL4. J Biol Chem 300(8):107541 |
| abstractText | 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 eta-secretase or MT5-MMP, which was described to generate so-called Aeta fragments. The similarity in large APP C-terminal fragments between both proteases raised the question of whether RHBDL4 may contribute to eta-secretase activity and Aeta-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 Aeta-like fragments in vitro without contributions of alpha-, beta-, or gamma-secretases. Such Aeta-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 Aeta fragments in dissociated mixed cortical cultures from WT mice, however significantly fewer Aeta fragments in RHBDL4 knockout cultures. Our data underscores that RHBDL4 contributes to the eta-secretease-like processing of APP and that RHBDL4 is a physiologically relevant protease for APP. |
