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Molecular and Cellular Biology, January 2003, p. 163-177, Vol. 23, No. 1
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.1.163-177.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Induction of Apoptosis by Sphingoid Long-Chain Bases in Aspergillus nidulans

Jijun Cheng,{dagger} Tae-Sik Park,{ddagger} Li-Chun Chio, Anthony S. Fischl, and Xiang S. Ye*

Infectious Diseases Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285

Received 22 July 2002/ Returned for modification 20 August 2002/ Accepted 30 September 2002

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.

* Corresponding author. Mailing address: Oncology Division, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285. Phone: (317) 277-1467. Fax: (317) 276-1414. E-mail: Ye_Xiang{at}lilly.com.

{dagger} Present address: Achillion Pharmaceuticals, Inc., New Haven, CT 06511.

{ddagger} Present address: Pfizer Global Research and Development, Department of Cardiovascular Pharmacology, Ann Arbor, MI 48105.

Molecular and Cellular Biology, January 2003, p. 163-177, Vol. 23, No. 1
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.1.163-177.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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