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 protein secretion and the disruption of the structure and function of organelles along the exocytic and endocytic pathways including the Golgi complex. Such effects of BFA have been ascribed in large part to its ability to prevent recruitment of cytosolic coat proteins onto organelle membranes. Here we show that mammalian cell lines differ from one another 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 from which the cell line originates, rather than on the cell line itself. In each cell line, the dose of BFA 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 vesicles, but not that for inhibition of binding of gamma-adaptin, a component of HA-I/AP-1 adaptor of clathrin-coated vesicles. These observations suggest that: (i) there are at least two targets for BFA that differ from each other in sensitivity to this drug, (ii) the difference in the sensitivity to BFA of the beta-COP binding is determined by the difference 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.
Torii
S
S
Institute of Applied Biochemistry, University of Tsukuba, Ibaraki, Japan.
Banno
T
T
Watanabe
T
T
Ikehara
Y
Y
Murakami
K
K
Nakayama
K
K
D016475:3T3 Cells; D033982:Adaptor Protein Complex gamma Subunits; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D020126:Brefeldin A; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects*; D002522:Chlorocebus aethiops; D020756:Coatomer Protein; D006224:Cricetinae; D003517:Cyclopentanes / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007668:Kidney; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D014407:Tumor Cells, Cultured
D033982:Adaptor Protein Complex gamma Subunits; D000900:Anti-Bacterial Agents; D020756:Coatomer Protein; D003517:Cyclopentanes; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D020126:Brefeldin A