CYTOTOXICITY OF BREFELDIN-A CORRELATES WITH ITS INHIBITORY EFFECT ON MEMBRANE-BINDING OF COP COAT PROTEINS

The fungal metabolite brefeldin A (BFA) causes the inhibition of prote in secretion and the disruption of the structure and function of organ elles along the exocytic and endocytic pathways including the Golgi co mplex. Such effects of BFA have been ascribed in large part to its abi lity to prevent recruitment of cytosolic coat proteins onto organelle membranes. Here we show that mammalian cell lines differ from one anot her with respect to sensitivity to this drug. The BFA sensitivity of a given cell line appears to be dependent on the species or the order f rom which the cell line originates, rather than on the cell line itsel f. In each cell line, the dose of EFA required for inhibition of cell growth and of protein secretion correlates with the dose required for inhibition of binding of beta-COP, a coat protein of COP-coated vesicl es, but not that for inhibition of binding of gamma-adaptin, a compone nt of HA-I/AP-1 adaptor of clathrin-coated vesicles. These observation s suggest that: (i) there are at least two targets for EFA that differ from each other in sensitivity to this drug, (ii) the difference in t he sensitivity to BFA of the beta-COP binding is determined by the dif ference in the structure of a target protein for this drug, and (iii) the cytotoxicity of BFA is ascribed mainly to its inhibitory effect on the membrane binding of COP-coat proteins.