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

Sutterwala, Shaheen; Creswell, Caleb H.; Sanyal, Sumana; Menon, Anant K.; Bangs, James D.

doi:10.1128/ec.00283-06

Cited by 40 publications

(57 citation statements)

References 71 publications

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“…However, addition of exogenous ethanolamine cannot rescue the SPT2 defect in T. brucei procyclic cells (data not shown) or bloodstream forms (Sutterwala et al, 2007), and suggests that in this parasite, unlike in Leishmania, sphingolipids and long-chain bases themselves rather than their metabolites are indispensable.…”

Section: Journal Of Cell Science 121 (4)mentioning

confidence: 93%

“…Sphingolipid biosynthesis is required for efficient transport of GPI-anchored membrane proteins in S. cerevisiae (Bagnat et al, 2001;Obeid et al, 2002) but does not affect the transport of GPIanchored VSG in bloodstream T. brucei or HeLa cells, indicating that this requirement for exocytosis is not universal (Sutterwala et al, 2007). Further, the canonical requirement for sphingolipids in the formation of DRM in eukaryotic cells (Brown and London, 1998;Ikonen, 2001;Simons and Toomre, 2000;van Meer and Lisman, 2002) has been challenged in Leishmania, where the association of GPI-anchored protein gp63 with DRMs is not affected in SPT2-null promastigotes (Denny et al, 2001;Zhang et al, 2003).…”

Section: Vesicular Trafficking Defects and Drmsmentioning

confidence: 99%

“…Further, sphingolipidenriched signaling platforms promote activation of kinases Src and PLC␥ which are essential to cytokinesis (Ng et al, 2005). However, myriocin treatment of bloodform T. brucei does not inhibit cytokinesis but rather arrests cell growth and replication in all stages of the cell cycle (Sutterwala et al, 2007).…”

Section: Journal Of Cell Science 121 (4)mentioning

confidence: 99%

“…(2) The glycoinositolphospholipids (GIPLs) may be upregulated to compensate for sphingolipid deficiency and, (3) GPI-linked raftassociated molecules are abundant in the plasma membrane. Intriguingly, sphingolipid biosynthesis is not essential for exocytosis in bloodstream forms of T. brucei or HeLa cells (Sutterwala et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Sphingolipid synthesis is necessary for kinetoplast segregation and cytokinesis in Trypanosoma brucei

Fridberg

Olson

Nakayasu

et al. 2008

Journal of Cell Science

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Sphingolipids and their metabolites have been thought crucial for cell growth and cell cycle progression, membrane and protein trafficking, signal transduction, and formation of lipid rafts; however, recent studies in trypanosomes point to the dispensability of sphingolipids in some of these processes. In this study, we explore the requirements for de novo sphingolipid biosynthesis in the insect life cycle stage of the African trypanosome Trypanosoma brucei by inhibiting the enzyme serine palmitoyltransferase (SPT2) by using RNA interference or treatment with a potent SPT2 inhibitor myriocin. Mass spectrometry revealed that upon SPT2 inhibition, the parasites contained substantially reduced levels of inositolphosphorylceramide. Although phosphatidylcholine and cholesterol levels were increased to compensate for this loss, the cells were ultimately not viable. The most striking result of sphingolipid reduction in procyclic T. brucei was aberrant cytokinesis, characterized by incomplete cleavage-furrow formation, delayed kinetoplast segregation and emergence of cells with abnormal DNA content. Organelle replication continued despite sphingolipid depletion, indicating that sphingolipids act as second messengers regulating cellular proliferation and completion of cytokinesis. Distention of the mitochondrial membrane, formation of multilamellar structures within the mitochondrion and near the nucleus, accumulation of lipid bodies and, less commonly, disruption of the Golgi complex were observed after prolonged sphingolipid depletion. These findings suggest that some aspects of vesicular trafficking may be compromised. However, flagellar membrane targeting and the association of the flagellar membrane protein calflagin with detergent-resistant membranes were not affected, indicating that the vesicular trafficking defects were mild. Our studies indicate that sphingolipid biosynthesis is vital for cell cycle progression and cell survival, but not essential for the normal trafficking of flagellar membrane-associated proteins or lipid raft formation in procyclic T. brucei.

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Section: Journal Of Cell Science 121 (4)mentioning

confidence: 93%

Section: Vesicular Trafficking Defects and Drmsmentioning

confidence: 99%

Section: Journal Of Cell Science 121 (4)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Sphingolipid synthesis is necessary for kinetoplast segregation and cytokinesis in Trypanosoma brucei

Fridberg

Olson

Nakayasu

et al. 2008

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…Moreover, there are several lines of evidence that these lipids have critical roles in trypanosomatids. Endogenous sterols and sphingolipids are required for proliferation of trypanosomes [38][39][40]. Interestingly, reduced inositolphosphoceramide (IPC) levels due to inhibition of serine palmitoyltransferase (Spt2) in T. brucei have been shown to be compensated for by increased levels of phosphatidylcholine and cholesterol, demonstrating a tight interaction of sterol and sphingolipid homeostasis [41].…”

Section: Systems-based Matchmakingmentioning

confidence: 99%