Cyclosporin A: new insights for cell biologists and biochemists

Cyclosporin A (CSA) is well known for its potent immunosuppressive properties. Until recently, most of the research on the mechanism of action of CSA focused on its effects on cytokine transcription by T lymphocytes. However, CSA inhibits a variety of other cellular functions. An intracellular CSA-binding protein, called cyclophilin, has been purified and characterized. This protein is found in nearly all mammalian cells, which suggests that it is involved in highly conserved cellular functions. The current concept is that CSA mediates its effect via cyclophilin. Cyclophilin is actually a peptidyl-prolyl cis-trans isomerase (PPIase), an enzyme proposed to catalyze protein folding. Because the binding of CSA to cyclophilin/PPIase in vitro inhibits the isomerase activity, it is thought that this may account for the inhibitory effects of CSA on the cellular functions described above. To add to the puzzle, a new immunosuppressive drug, FK-506, has recently been shown to bind to an intracellular protein similar to, but distinct from, cyclophilin. The FK-506 binding protein also has a PPIase activity, and this activity is inhibited by FK-506. These data are consistent with the hypothesis that CSA and FK-506 mediate their effects on cellular functions by inhibiting an isomerase activity required for protein folding. This hypothesis poses several interesting questions. For example, how is this protein folding step involved in such diverse cellular functions as gene transcription and granule exocytosis? Verification of the role of CSA and PPIase in cellular functions awaits the identification of the substrates for the isomerases.