Figure 1. LOX-1 cleavage by the intramembrane proteases SPPL2a/b is athero-protective. (A) After proteolytic cleavage of the LOX-1 ectodomain, the remaining N-terminal fragment (NTF) is further processed by the intramembrane proteases Signal peptide peptidase-like 2a/b (SPPL2a/b). Thereby, the LOX-1 intracellular domain (ICD) is released into the cytosol. In SPPL2a/b-deficient cells, the uncleaved LOX-1 NTF accumulates in the membrane. (B) LOX-1 is a receptor for oxidized LDL (oxLDL). Following binding of oxLDL, LOX-1 triggers pro-atherogenic MAP kinase signalling, which can be enhanced by accumulating NTFs in SPPL2a/b-deficient cells. In parallel, the LOX-1 NTF can signal autonomously in a ligand-independent way.