Tiki proteins are glycosylphosphatidylinositol-anchored proteases

Wnt signalling pathways play pivotal roles in development, homeostasis and human diseases, and are tightly regulated. We previously identified Tiki as a novel family of Wnt inhibitory proteases. Tiki proteins were predicted as type I transmembrane proteins and can act in both Wnt-producing and Wnt-responsive cells. Here, we characterize Tiki proteins as glycosylphosphatidylinositol (GPI)-anchored proteases. TIKI1/2 proteins are enriched on the detergent-resistant membrane microdomains and can be released from the plasma membrane by GPI-specific glycerophosphodiesterases GDE3 and GDE6, but not by GDE2. The GPI anchor determines the cellular localization of Tiki proteins and their regulation by GDEs, but not their inhibitory activity on Wnt signalling. Our study uncovered novel characteristics and potential regulations of the Tiki family proteases.