Abstract
Fucose is a common component of eukaryotic cell-surface glycoconjugates, generally added by Golgi-resident fucosyltransferases. Whereas fucosylated glycoconjugates are rare in kinetoplastids, the biosynthesis of the nucleotide sugar GDP-Fuc has been shown to be essential in Trypanosoma brucei. Here we show that the single identifiable T. brucei fucosyltransferase (TbFUT1) is a GDP-Fuc: β-D-galactose α-1,2-fucosyltransferase with an apparent preference for a Galβ1,3GlcNAcβ1-O-R acceptor motif. Conditional null mutants of TbFUT1 demonstrated that it is essential for both the mammalian-infective bloodstream form and the insect vector-dwelling procyclic form. Unexpectedly, TbFUT1 was localized in the mitochondrion of T. brucei and found to be required for mitochondrial function in bloodstream form trypanosomes. Finally, the TbFUT1 gene was able to complement a Leishmania major mutant lacking the homologous fucosyltransferase gene (Guo et al., 2021). Together these results suggest that kinetoplastids possess an unusual, conserved and essential mitochondrial fucosyltransferase activity that may have therapeutic potential across trypanosomatids.
Highlights
The protozoan parasites of the Trypanosoma brucei group are the causative agents of human and animal African trypanosomiasis
The surface coat of the bloodstream form is characterized by the GPI-a nchored, N-glycosylated and occasionally O-glycosylated variant surface glycoprotein (VSG) (Cross, 1996; Mehlert et al, 1998; Pays and Nolan, 1998; Pinger et al, 2018; Schwede and Carrington, 2010), while procyclic cells express a family of GPI-a nchored proteins called procyclins (Richardson et al, 1988; Roditi et al, 1998; Treumann et al, 1997; Vassella et al, 2001), free glycoinositolphospholipids (Nagamune et al, 2004; Roper et al, 2005; Vassella et al, 2003), and a high molecular weight glycoconjugate complex (Güther et al, 2009)
One or more sequences from each family were selected for BLASTp searches of the predicted proteins from the T. brucei, T. cruzi, and L. major genomes (Supplementary file 1)
Summary
The protozoan parasites of the Trypanosoma brucei group are the causative agents of human and animal African trypanosomiasis. GDP-fucose (GDP- Fuc) was identified in the nucleotide sugar pools of T. brucei, Trypanosoma cruzi, and Leishmania major (Turnock and Ferguson, 2007), and its biosynthesis is essential for parasite growth in procyclic and bloodstream form T. brucei (Turnock et al, 2007) and in L. major promastigotes (Guo et al, 2017). Despite the aforementioned essentialities for GDP-Fuc in T. brucei and L. major, the only structurally defined fucose-c ontaining oligosaccharide in trypanosomatids is the low-abundance Ser/Thr-phosphodiester-linked glycan on T. cruzi gp, a glycoprotein that has been implicated in flagellar attachment (Allen et al, 2013; Cooper et al, 1993; Ferguson et al, 1983; Haynes et al, 1996). Studies have shown that both mitochondrial OGT (mOGT) and OGA are present and active in mammalian mitochondria and putative mitochondrial targets have been identified (Banerjee et al, 2015; Sacoman et al, 2017). Similar results were obtained in the related trypanosomatid parasite L. major (Guo et al, 2021), extending this unexpected finding across the trypanosomatid protozoans
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