Addition of α-O-GlcNAc to threonine residues define the post-translational modification of mucin-like molecules in Trypanosoma cruzi

Abstract

Trypanosoma cruzi, an intracellular protozoan etiologic agent of Chagas disease is covered by a dense coat of mucin-type glycoproteins, which is important to promote the parasite entry and persistence in the mammalian host cells. The O-glycosylation of T. cruzi mucins (Tc-mucins) is initiated by enzymatic addition of α-O-N-acetylglucosamine (GlcNAc) to threonine (Thr) by the UDP-GlcNAc:polypeptide α-N-acetylglucosaminyltransferase (pp-α-GlcNAcT) in the Golgi. The Tc-mucin is characterized by the presence of a high structural diversity of O-linked oligosaccharides found among different parasite strains, comprising two O-glycan Cores. In the Core 1, from strains principally associated with the domestic transmission cycle of Chagas disease, the GlcNAc O-4 is substituted with a β-galactopyranose (βGalp) unit, and in the most complex oligosaccharides the GlcNAc O-6 is further processed by the addition of β1 → 2-linked Galp residues creating a short linear Galp-containing chain. In the Core 2 structures, expressed by strains isolated from T. cruzi sylvatic hosts, the GlcNAc O-4 carries a β-galactofuranose (βGalf) unit and the GlcNAc O-6 can carry a branched Galpβ1 → 3[Galpβ1 → 2]Galpβ1 → 6 motif. The O-glycans carrying nonreducing terminal βGalp are available for sialylation by a surface T. cruzi trans-sialidase activity. Based on structural results, this review summarizes available data on the highly conserved process, which adds the GlcNAc unit in α-linkage to Thr residues the basis of the post-translational modification system in T. cruzi mucins. In addition, a mechanism unique employed by the parasite to transfer exogenous sialic acid residues to Tc-mucins is presented.

Expanding the knowledge of the chemical structure of glycoconjugates from Trypanosoma cruzi TcI genotype. Contribution to taxonomic studies

“…GIPLs and mucin-like molecules are abundant in the membrane of parasitic protozoa that are common etiologic agents of medical and veterinary diseases (Ferguson 1997, Mendonça-Previato et al 2013, Giorgi and De Lederkremer 2011, Buscaglia et al 2006, DosReis et al 2002, Lederkremer and Bertello 2001. Although it has been known that structural differences exist in the composition of such molecules among different strains of T. cruzi (Mendonça-Previato et al 2013, Acosta-Serrano et al 2001, Frasch 2000, Lederkremer and Bertello 2001, there is scarce information regarding its immunobiological functions following the course of infection. In addition, so far, no one has described the relationship between the glycan composition vs. the biological effect of such parasitic glycoconjugates.…”

“…cruzi surface is coated by a layer of glycoconjugates that play a role in many biological processes like survival, infectivity and parasite permanence in the host (Mendonça-Previato et al 2013, 2008. Most glycoproteins and glycolipids are attached to the bilayer through glycophosphatidylinositol (GPI) anchors , Ferguson 1999 and are organized into large groups: glycoinositolphospholipids (De Lederkremer et al 1991, Previato et al 1990a, T. cruzi mucins (Tc-mucins) (Previato et al 1994(Previato et al , 1995 and trans-sialidases (Previato et al 1985, Schenkman et al 1991.…”

Immune Evasion Strategies ofTrypanosoma cruzi

“…The parasite surface is covered by mucin-like molecules with, attached to their terminal β -galactosyl residues, sialic acid residues which are transferred from host glycoconjugates by the parasite trans-sialidase [ 45 – 48 ]. These T. cruzi mucins are O-glycosylated Thr/Ser/Pro-rich proteins; they are the predominant glycoproteins on the parasite surface and are encoded by more than 800 genes comprising approximately 1% of the parasite genome [ 49 – 51 ].…”

Antibodies against Mucin‐Based Glycopeptides Affect Trypanosoma cruzi Cell Invasion and Tumor Cell Viability

“…Mucins found in Trypanosoma cruzi , the parasite responsible for Chagas disease, show some striking differences from those found in mammalian systems. These mainly relate to the peptide glycosylation pattern, in which the threonine or serine residues are O ‐linked to α‐ N‐ acetylglucosamine (αGlcNAc) units, further substituted by galactose (Gal) at the O‐4 and O‐6 positions (Scheme ), rather than to α‐ N ‐acetylgalactosamine (αGalNAc) substituted by Gal at the O‐3 and O‐6 positions as found in mammalian mucins 3–6. This αGlcNAc‐Ser/Thr core is not expressed in humans, so it might represent a crucial immunogen that could be explored for further immunotherapeutic/diagnostic strategies 7…”