Eukaryotic Cell
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Eukaryotic Cell, March 2007, p. 454-464, Vol. 6, No. 3
1535-9778/07/$08.00+0     doi:10.1128/EC.00283-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

De Novo Sphingolipid Synthesis Is Essential for Viability, but Not for Transport of Glycosylphosphatidylinositol-Anchored Proteins, in African Trypanosomes{triangledown}

Shaheen S. Sutterwala,1 Caleb H. Creswell,2 Sumana Sanyal,3 Anant K. Menon,3 and James D. Bangs1*

Department of Medical Microbiology and Immunology,1 Department of Biochemistry, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706,2 Department of Biochemistry, Weill Medical College of Cornell University, New York, New York 100213

Received 5 September 2006/ Accepted 20 December 2006

De novo sphingolipid synthesis is required for the exit of glycosylphosphatidylinositol (GPI)-anchored membrane proteins from the endoplasmic reticulum in yeast. Using a pharmacological approach, we test the generality of this phenomenon by analyzing the transport of GPI-anchored cargo in widely divergent eukaryotic systems represented by African trypanosomes and HeLa cells. Myriocin, which blocks the first step of sphingolipid synthesis (serine + palmitate -> 3-ketodihydrosphingosine), inhibited the growth of cultured bloodstream parasites, and growth was rescued with exogenous 3-ketodihydrosphingosine. Myriocin also blocked metabolic incorporation of [3H]serine into base-resistant sphingolipids. Biochemical analyses indicate that the radiolabeled lipids are not sphingomyelin or inositol phosphorylceramide, suggesting that bloodstream trypanosomes synthesize novel sphingolipids. Inhibition of de novo sphingolipid synthesis with myriocin had no adverse effect on either general secretory trafficking or GPI-dependent trafficking in trypanosomes, and similar results were obtained with HeLa cells. A mild effect on endocytosis was seen for bloodstream trypanosomes after prolonged incubation with myriocin. These results indicate that de novo synthesis of sphingolipids is not a general requirement for secretory trafficking in eukaryotic cells. However, in contrast to the closely related kinetoplastid Leishmania major, de novo sphingolipid synthesis is essential for the viability of bloodstream-stage African trypanosomes.

* Corresponding author. Mailing address: Department of Medical Microbiology and Immunology, University of Wisconsin—Madison Medical School, 1300 University Ave., Madison, WI 53706. Phone: (608) 262-3110. Fax: (608) 262-8418. E-mail: jdbangs{at}wisc.edu.

{triangledown} Published ahead of print on 12 January 2007.

Eukaryotic Cell, March 2007, p. 454-464, Vol. 6, No. 3
1535-9778/07/$08.00+0     doi:10.1128/EC.00283-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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