SPPL2A is an intramembrane-cleaving aspartic protease that catalyzes the cleavage of type II membrane proteins within their hydrophobic transmembrane domains 1. It functions as a regulatory protease processing multiple substrates including TNF, FasL, and critically, the CD74 invariant chain 2. SPPL2A cleaves the N-terminal fragment (NTF) of CD74 accumulated in antigen-presenting cells, with this degradation essential for dendritic cell development and immune function 23. Structurally, SPPL2A comprises nine transmembrane helices with a conserved aspartyl protease fold; substrate binding triggers conformational rearrangements facilitating catalysis 4. Beyond immune regulation, SPPL2A processes LOX-1 NTFs to suppress pro-atherogenic signaling, with SPPL2A deficiency exacerbating atherosclerosis development 5. N-terminal protease-associated (PA) domains mediate substrate recognition and discrimination among homologous SPPL proteases 6. Clinically, biallelic SPPL2A loss-of-function mutations cause Immunodeficiency 86, characterized by mycobacterial susceptibility due to selective depletion of conventional dendritic cell subset 2 (cDC2) and impaired IFN-γ production 2. Machine learning analysis identified SPPL2A as a novel locus associated with Alzheimer's disease risk 7. These findings establish SPPL2A as a multifunctional proteolytic regulator of immune homeostasis, cardiovascular health, and potentially neurodegeneration.