SPPL2C is a testis-specific aspartyl intramembrane protease that plays crucial roles in male fertility through both catalytic and non-catalytic mechanisms 1. The protein exhibits proteolytic activity towards tail-anchored proteins and cleaves substrates with type II transmembrane topology, similar to other SPP/SPPL family members 23. SPPL2C's catalytic activity is uniquely regulated by the ER chaperone calnexin, which binds specifically to its N-glycosylated protease-associated domain and is essential for intramembrane proteolysis 1. The protease cleaves several physiologically relevant substrates including phospholamban (PLN), which regulates SERCA2 and intracellular calcium homeostasis, and various SNARE proteins involved in vesicular trafficking 23. In male germ cells, SPPL2C deficiency leads to partial loss of elongated spermatids, reduced sperm motility, and impaired vesicular transport due to SNARE protein cleavage, though fertility is preserved 23. The protein also functions as a scaffold supporting FREY1 in IZUMO1 recruitment for acrosome assembly during spermatogenesis. Beyond reproductive function, SPPL2C shows associations with brain glymphatic system function and neurodegenerative diseases, suggesting broader physiological roles 45.