Protein O- and C-Glycosylation pathways in Toxoplasma gondii and Plasmodium falciparum

Bandini, Giulia; Albuquerque-Wendt, Andreia; Hegermann, Jan; Samuelson, John; Routier, Françoise H.

doi:10.1017/s0031182019000040

Cited by 34 publications

(29 citation statements)

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“…Apart from CD35, CD44, and CD55, we found several merozoite receptors, including basigin, intercellular adhesion molecule 4, and glycophorin-A (GPA), that were extensively N -glycosylated in the early stages of parasite development ( supplemental Dataset S27 ). Because P. falciparum lacks sufficient glycosylation enzymes, the modifications of erythrocytic proteins were likely triggered by signaling during parasite invasion ( 53 ).…”

Section: Resultsmentioning

confidence: 99%

Protein Modification Characteristics of the Malaria Parasite Plasmodium falciparum and the Infected Erythrocytes

Wang

Jiang

Sang

et al. 2021

Molecular & Cellular Proteomics

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Malaria elimination is still pending on the development of novel tools that rely on a deep understanding of parasite biology. Proteins of all living cells undergo a myriad number of posttranslational modifications (PTMs) that are critical to multifarious life processes. An extensive proteome-wide dissection revealed a fine PTM map of most proteins in both Plasmodium falciparum, the causative agent of severe malaria, and the infected red blood cells. More than two-thirds of proteins of the parasite and its host cell underwent extensive and dynamic modification throughout the erythrocytic developmental stage. PTMs critically modulate the virulence factors involved in the host-parasite interaction and pathogenesis. Furthermore, P. falciparum stabilized the supporting proteins of erythrocyte origin by selective de-modification. Collectively, our multiple omic analyses, apart from having furthered a deep understanding of the systems biology of P. falciparum and malaria pathogenesis, provide a valuable resource for mining new antimalarial targets.

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Section: Resultsmentioning

confidence: 99%

Protein Modification Characteristics of the Malaria Parasite Plasmodium falciparum and the Infected Erythrocytes

Wang

Jiang

Sang

et al. 2021

Molecular & Cellular Proteomics

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“…Spy (TGME49_273500) (63) is an enzyme similar to O-linked N-acetylglucosamine transferase (OGT) that mediates O-linked ␤-N-acetylglucosaminylation. O-linked ␤-N-acetylglucosaminylation is a posttranslational modification of cytosolic, nuclear, and mitochondrial proteins by a single residue of N-acetylglucosamine which is transferred from UDP-N-acetylglucosamine and is hypothesized to be involved in the localization of nuclear proteins (64,65). O-linked ␤-N-acetylglucosaminylation is reversible by O-linked ␤-Nacetylglucosaminyl hydrolase (OGA), which removes the N-acetylglucosamine residue (66).…”

Section: Discussionmentioning

confidence: 99%

Succinylated Wheat Germ Agglutinin Colocalizes with the Toxoplasma gondii Cyst Wall Glycoprotein CST1

Guevara

Fox

Bzik

2020

mSphere

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The glycosylated mucin domain of the Toxoplasma gondii cyst wall glycoprotein CST1 is heavily stained by Dolichos biflorus agglutinin, a lectin that binds to N-acetylgalactosamine. The cyst wall is also heavily stained by the chitin binding lectin succinylated wheat germ agglutinin (s-WGA), which selectively binds to N-acetylglucosamine-decorated structures. Here, we tracked the localization of N-acetylglucosamine-decorated structures that bind to s-WGA in immature and mature in vitro cysts. s-WGA localization was observed at the cyst periphery 6 h after the differentiation of the tachyzoite-stage parasitophorous vacuole. By day 1 and at all later times after differentiation, s-WGA was localized in a continuous staining pattern at the cyst wall. Coinciding with the maturation of the cyst matrix by day 3 of cyst development, s-WGA also localized in a continuous matrix pattern inside the cyst. s-WGA localized in both the outer and inner layer regions of the cyst wall and in a continuous matrix pattern inside mature 7-and 10-day-old cysts. In addition, s-WGA colocalized in the cyst wall with CST1, suggesting that N-acetylglucosamineand N-acetylgalactosamine-decorated molecules colocalized in the cyst wall. In contrast to CST1, GRA4, and GRA6, the relative accumulation of the molecules that bind s-WGA in the cyst wall was not dependent on the expression of GRA2. Our results suggest that GRA2-dependent and GRA2-independent mechanisms regulate the trafficking and accumulation of glycosylated molecules that colocalize in the cyst wall. IMPORTANCE Chronic Toxoplasma gondii infection is maintained in the central nervous system by thick-walled cysts. If host immunity wanes, cysts recrudesce and cause severe and often lethal toxoplasmic encephalitis. Currently, there are no therapies to eliminate cysts, and little biological information is available regarding cyst structure(s). Here, we investigated cyst wall molecules recognized by succinylated wheat germ agglutinin (s-WGA), a lectin that specifically binds to N-acetylglucosamine-decorated structures. N-Acetylglucosamine regulates cell signaling and plays structural roles at the cell surface in many organisms. The cyst wall and cyst matrix were heavily stained by s-WGA in mature cysts and were differentially stained during cyst development. The relative accumulation of molecules that bind to s-WGA in the cyst wall was not dependent on the expression of GRA2. Our findings suggest that glycosylated cyst wall molecules gain access to the cyst wall via GRA2-dependent and GRA2-independent mechanisms and colocalize in the cyst wall.

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“…Additionally, TRAP was also shown to be modified by an additional hexose (presumably C -linked mannose) in P. falciparum (Swearingen et al ., 2016) but, interestingly, not in P. vivax (Swearingen et al ., 2017). These, and other works (Sanz et al ., 2013; Cova et al ., 2015; Bandini et al ., 2019), are renewing the interest of the Plasmodium research community on the extent and relevance of the parasite glycosylation.…”

Section: Introductionmentioning

confidence: 99%

A Plasmodium falciparum C-mannosyltransferase is dispensable for parasite asexual blood stage development

2019

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C-mannosylation was recently identified in the thrombospondin-related anonymous protein (TRAP) from Plasmodium falciparum salivary gland sporozoites. A candidate P. falciparum C-mannosyltransferase (PfDPY-19) was demonstrated to modify thrombospondin type 1 repeat (TSR) domains in vitro, exhibiting a different acceptor specificity than their mammalian counterparts. According to the described minimal acceptor of PfDPY19, several TSR domain-containing proteins of P. falciparum could be C-mannosylated in vivo. However, the relevance of this protein modification for the parasite viability remains unknown. In the present study, we used CRISPR/Cas9 technology to generate a PfDPY19 null mutant, demonstrating that this glycosyltransferase is not essential for the asexual blood development of the parasite. PfDPY19 gene disruption was not associated with a growth phenotype, not even under endoplasmic reticulum-stressing conditions that could impair protein folding. The data presented in this work strongly suggest that PfDPY19 is unlikely to play a critical role in the asexual blood stages of the parasite, at least under in vitro conditions.

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Protein O- and C-Glycosylation pathways in Toxoplasma gondii and Plasmodium falciparum

Cited by 34 publications

References 100 publications

Protein Modification Characteristics of the Malaria Parasite Plasmodium falciparum and the Infected Erythrocytes

Protein Modification Characteristics of the Malaria Parasite Plasmodium falciparum and the Infected Erythrocytes

Succinylated Wheat Germ Agglutinin Colocalizes with the Toxoplasma gondii Cyst Wall Glycoprotein CST1

A Plasmodium falciparum C-mannosyltransferase is dispensable for parasite asexual blood stage development

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