Catalyzes intramembrane proteolysis of some signal peptides after they have been cleaved from a preprotein, resulting in the release of the fragment from the ER membrane into the cytoplasm. Required to generate lymphocyte cell surface (HLA-E) epitopes derived from MHC class I signal peptides. Involved in the intramembrane cleavage of the integral membrane protein PSEN1. Cleaves the integral membrane protein XBP1 isoform 1 in a DERL1/RNF139-dependent manner (By similarity). May play a role in graft rejection (PubMed:9354467). Monomer. Homodimer (By similarity). Interacts with RNF139 (PubMed:19720873). Interacts with DERL1 and XBP1 isoform 1 (By similarity). Widely expressed with highest levels in liver and kidney. In the brain, expressed predominantly in hippocampus, amygdala, piriform cortex, choroid plexus and arcuate nucleus of the hypothalamic area. Isoform 1 is more strongly expressed than isoform 4 in most tissues except brain and skeletal muscle where isoform 4 is the dominant isoform and in testis where isoform 1 and isoform 4 are expressed at similar levels. In the brain, isoform 4 is not detected in the choroid plexus. In the embryo, expression starts at day 6.5. The first transmembrane domain may act as a type I signal anchor. The PAL motif is required for normal active site conformation. Belongs to the peptidase A22B family.