DISTINCTIVE INHIBITION OF THE LYSOSOMAL TARGETING OF LYSOZYME AND CATHEPSIN-D BY DRUGS AFFECTING PH GRADIENTS AND PROTEIN-KINASE-C

Morphological and biochemical evidence indicates that in several cell types, lysozyme is found in both lysosomes and the medium. Here we rep ort that in calcitriol-treated human promonocytes U937, in which appro x. two-thirds of the synthesized lysozyme is secreted, most of the int racellular lysozyme co-localizes with cathepsin D in lysosomal organel les. In the presence of NH4Cl the lysosomal targeting of procathepsin D, but not that of lysozyme, is inhibited. In the presence of 4 beta-p horbol 12-myristate 13-acetate (4 beta-PMA; 'TPA'), the lysosomal pack aging of lysozyme is almost completely inhibited, while that of procat hepsin D is only partially so. However, the inhibition of the lysosoma l targeting of procathepsin D by NH4Cl and 4 beta-PMA is additive. The targeting of lysozyme is partially inhibited in the presence of R-590 22, an inhibitor of diacylglycerol kinase, whereas it is not affected by 4 alpha-phorbol 12-myristate 13-acetate, an isomer of 4 beta-PMA th at does not activate protein kinase C. It is concluded that in U937 ce lls both carbohydrate-dependent and -independent recognition contribut es to the lysosomal targeting of soluble proteins. We suggest that the carbohydrate-independent traffic of proteins to lysosomal compartment s is controlled by a signalling pathway involving protein kinase C.