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Eukaryotic Cell, December 2008, p. 2147-2159, Vol. 7, No. 12
1535-9778/08/$08.00+0     doi:10.1128/EC.00147-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Stress-Induced Cell Death Is Mediated by Ceramide Synthesis in Neurospora crassa{triangledown}

Nora S. Plesofsky,1* Steven B. Levery,2,{dagger} Sherry A. Castle,2 and Robert Brambl1

Department of Plant Biology, University of Minnesota, Saint Paul, Minnesota 55108,1 Department of Chemistry, University of New Hampshire, Durham, New Hampshire 038242

Received 25 April 2008/ Accepted 17 October 2008

The combined stresses of moderate heat shock (45°C) and analog-induced glucose deprivation constitute a lethal stress for Neurospora crassa. We found that this cell death requires fatty acid synthesis and the cofactor biotin. In the absence of the cofactor, the stressed cells are particularly sensitive to exogenous ceramide, which is lethal at low concentrations. When we extracted endogenous sphingolipids, we found that unique ceramides were induced (i) by the inhibitory glucose analog 2-deoxyglucose and (ii) by combined heat shock and 2-deoxyglucose. We determined that the former is a 2-deoxyglucose-modified ceramide. By structural analysis, we identified the latter, induced by dual stress, as C18(OH)-phytoceramide. We also identified C24(OH)-phytoceramide as a constitutive ceramide that continues to be produced during the combined stresses. The unusual C18(OH)-phytoceramide is not made by germinating asexual spores subjected to the same heat and carbon stress. Since these spores, unlike growing cells, do not die from the stresses, this suggests a possible connection between synthesis of the dual-stress-induced ceramide and cell death. This connection is supported by the finding that a (dihydro)ceramide synthase inhibitor, australifungin, renders cells resistant to death from these stresses. The OS-2 mitogen-activated protein kinase, homologous to mammalian p38, may be involved in the cell death signaling pathway. Strains lacking OS-2 survived the combined stresses better than the wild type, and phosphorylated OS-2 increased in wild-type cells in response to heat shock and combined heat and carbon stress.

* Corresponding author. Mailing address: Department of Plant Biology, 1445 Gortner Avenue, St. Paul, MN 55108. Phone: (612) 624-5375. Fax: (612) 625-1738. E-mail: norap{at}umn.edu

{triangledown} Published ahead of print on 24 October 2008.

{dagger} Present address: Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark.

Eukaryotic Cell, December 2008, p. 2147-2159, Vol. 7, No. 12
1535-9778/08/$08.00+0     doi:10.1128/EC.00147-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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