A general strategy is presented for the dominant negative reduction in the levels of heterodimeric soluble proteins within the secretory pathway through fusion of one of its partners C-terminal to the lysosomal enzyme cathepsin B (CB). Stable transfectants of CB-7B2 chimeras in AT20 cells result in a drastic reduction of the endogenous levels of its partner, the proprotein convertase PC2. This dominant negative suppressive effect requires active CB. It was partially reversed by NH4Cl, the cell-permeable CB inhibitor CA-074Me, but not by the proteasome inhibitor Lactacystin, suggesting the potential participation of the lysosomal/endosomal degradative pathway in this process.