Transport-dependent proteolysis of SREBP: Relocation of Site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi

Cholesterol homeostasis in animal cells is achieved by regulated cleavage o f membrane-bound transcription factors, designated SREBPs. Proteolytic rele ase of the active domains of SREBPs from membranes requires a sterol-sensin g protein, SCAP, which forms a complex with SREBPs. In sterol-depleted cell s, SCAP escorts SREBPs from ER to Golgi, where SREBPs are cleaved by Site-1 protease (S1P). Sterols block this transport and abolish cleavage. Relocat ing active S1P from Golgi to ER by treating cells with brefeldin A or by fu sing the ER retention signal KDEL to S1P obviates the SCAP requirement and renders cleavage insensitive to sterols. Transport-dependent proteolysis ma y be a common mechanism to regulate the processing of membrane proteins.