The essential neutral sphingomyelinase is involved in trafficking of the variant surface glycoprotein in the bloodstream form of Trypanosoma brucei

Autor: Young, Simon Alan, Smith, Terry K.
Přispěvatelé: Centre for Biomolecular Sciences, University of St Andrews [Scotland]
Jazyk: angličtina
Rok vydání: 2010
Předmět:
Zdroj: Molecular Microbiology
Molecular Microbiology, Wiley, 2010, 76 (6), pp.1461. ⟨10.1111/j.1365-2958.2010.07151.x⟩
ISSN: 0950-382X
1365-2958
DOI: 10.1111/j.1365-2958.2010.07151.x⟩
Popis: International audience; Sphingomyelin is the main sphingolipid in Trypanosoma brucei, the causative agent of African sleeping sickness. In vitro and in vivo characterisation of the T.brucei neutral sphingomyelinase demonstrates that it is directly involved in sphingomyelin catabolism. Gene knockout studies in the bloodstream form of the parasite indicate that the neutral sphingomyelinase is essential for growth and survival, thus highlighting that the de novo biosynthesis of ceramide is unable to compensate for the loss of sphingomyelin catabolism. The phenotype of the conditional knockout has given new insights into the highly active endocytic and exocytic pathways in the bloodstream form of T.brucei. Hence, the formation of ceramide in the ER affects post-Golgi sorting and rate of deposition of newly synthesised GPI-anchored variant surface glycoprotein on the cell-surface. This directly influences the corresponding rate of endocytosis, via the recycling endosomes, of pre-existing cell-surface variant surface glycoprotein. The trypanosomes use this coupled endocytic and exocytic mechanism to maintain the cell-density of its crucial variant surface glycoprotein protective coat. TbnSMase is therefore genetically validated as a drug target against African trypanosomes, and suggests that interfering with the endocytic transport of variant surface glycoprotein is a highly desirable strategy for drug development against African trypanosomasis.
Databáze: OpenAIRE
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