Induction of apoptosis by sphingoid long-chain bases in Aspergillus nidulans.
Sphingolipid metabolism is implicated to play an important role in apoptosis. Here we show that dihydrosphingosine (DHS) and phytosphingosine (PHS), two major sphingoid bases of fungi, have potent fungicidal activity with remarkably high structural and stereochemical specificity against Aspergillus nidulans. In fact, only naturally occurring DHS and PHS are active. Further analysis revealed that DHS and PHS induce rapid DNA condensation independent of mitosis, large-scale DNA fragmentation, and exposure of phosphatidylserine, all common morphological features characteristic of apoptosis, suggesting that DHS and PHS induce apoptosis in A. nidulans. The finding that DNA fragmentation requires protein synthesis, which implies that an active process is involved, further supports this proposition. The induction of apoptosis by DHS and PHS is associated with the rapid accumulation of reactive oxygen species (ROS). However, ROS are not required for apoptosis induced by DHS and PHS, as scavenging of ROS by a free radical spin trap has no effect. We further demonstrate that apoptosis induced by DHS and PHS is independent of metacaspase function but requires mitochondrial function. Together, the results suggest that DHS and PHS induce a type of apoptosis in A. nidulans most similar to the caspase-independent apoptosis observed in mammalian systems. As A. nidulans is genetically tractable, this organism should be an ideal model system for dissecting sphingolipid signaling in apoptosis and, importantly, for further elucidating the molecular basis of caspase-independent apoptosis.
Cheng
Jijun
J
Infectious Diseases Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Park
Tae-Sik
TS
Chio
Li-Chun
LC
Fischl
Anthony S
AS
Ye
Xiang S
XS
D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001233:Aspergillus nidulans / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D001483:Base Sequence; D015415:Biomarkers; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D053938:DNA Fragmentation; D004271:DNA, Fungal / Q000187:drug effects; D005656:Fungal Proteins / Q000096:biosynthesis / Q000235:genetics; D017353:Gene Deletion; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008938:Mitosis; D008969:Molecular Sequence Data; D009154:Mutation; D017382:Reactive Oxygen Species / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D015415:Biomarkers; D004271:DNA, Fungal; D005656:Fungal Proteins; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D020169:Caspases; C456272:MCA1 protein, S cerevisiae; C012491:phytosphingosine; D013110:Sphingosine; C005682:safingol