Self-Protection against the Sphingolipid Biosynthesis Inhibitor Fumonisin B 1 Is Conferred by a FUM Cluster-Encoded Ceramide Synthase

Fumonisin (FB) mycotoxins produced by species of the genus detrimentally affect human and animal health upon consumption, due to the inhibition of ceramide synthase. In the present work, we set out to identify mechanisms of self-protection employed by the FB producer FB biosynthesis was shown to be compartmentalized, and two cluster-encoded self-protection mechanisms were identified. First, the ATP-binding cassette transporter Fum19 acts as a repressor of the gene cluster. Appropriately, deletion and overexpression increased and decreased, respectively, the levels of intracellular and secreted FB Second, the cluster genes and were shown to be two of five ceramide synthase homologs in , grouping into the two clades CS-I and CS-II in a phylogenetic analysis. The ability of to fully complement the yeast ceramide synthase null mutant / demonstrated its functionality, while coexpression of and partially complemented, likely via heterodimer formation. Cell viability assays revealed that Fum18 contributes to the fungal self-protection against FB and increases resistance by providing cluster-encoded ceramide synthase activity. The biosynthesis of fungal natural products is highly regulated not only in terms of transcription and translation but also regarding the cellular localization of the biosynthetic pathway. In all eukaryotes, the endoplasmic reticulum (ER) is involved in the production of organelles, which are subject to cellular traffic or secretion. Here, we show that in , early steps in fumonisin production take place in the ER, together with ceramide biosynthesis, which is targeted by the mycotoxin. A first level of self-protection is given by the presence of a cluster-encoded ceramide synthase, Fum18, hitherto uncharacterized. In addition, the final fumonisin biosynthetic step occurs in the cytosol and is thereby spatially separate from the fungal ceramide synthases. We suggest that these strategies help the fungus to avoid self-poisoning during mycotoxin production.