The role of GPI-anchored LY6/uPAR family proteins in connecting membrane microdomains with immune regulation and diseases.

Glycosylphosphatidylinositol (GPI)-anchored LY6/uPAR family proteins are structurally conserved yet functionally diverse regulators of immune signaling. Defined by a characteristic three-finger LY6/uPAR (LU) domain and preferential localization to lipid rafts, members such as LY6A, LY6C, LY6E, LY6G, CD59, PSCA, and uPAR orchestrate essential immune processes, including T and B cell activation, dendritic cell maturation, neutrophil and natural killer (NK) cell responses, and macrophage polarization. These proteins are increasingly implicated in the pathogenesis of cancer, infectious diseases, autoimmune disorders, and neuroinflammation. GPI anchoring facilitates receptor pre-orientation, nanocluster formation, and rapid signal transduction within membrane microdomains, thereby enabling precise spatial and temporal control of immune signaling. Several LY6/uPAR members have emerged as promising clinical targets, with translational strategies encompassing CAR-T cell therapies, antibody-drug conjugates, and lipid raft-modulating agents. This review presents a comprehensive overview of current knowledge, linking the structural, spatial, and functional characteristics of LY6/uPAR proteins to their relevance in health and disease, identifying key unresolved mechanistic questions, and underscoring emerging translational opportunities within the context of precision immunology.