Intramembrane proteolysis is now widely recognized as an important physiological pathway required for reverse signaling and membrane protein degradation. Aspartyl intramembrane cleaving proteases of the GXGD-type play an important regulatory role in health and disease. Signal peptide peptidase (SPP) and SPP-like (SPPL) peptidases, such as SPPL2a, SPPL2b, IMP5, and SPPL3, belong to the family of GXGD aspartic proteases. The putative catalytic domains of SPP and SPPLs are embedded in membranes in an orientation predisposed to cleave type II oriented transmembrane proteins. IMP5 (intramembrane protease 5), also known as SPPL2c (signal peptide peptidase-like 2C), is a 690 amino acid multi-pass membrane protein that may act as an intramembrane protease. IMP5 also belongs to the peptidase A22B family and two isoforms are produced by alternative splicing events.