Identification of Key Players that Cause Ricin Toxicity by Comparative Glycoproteomics

Although significant advances have been made in genomics, metabolomics, protein and lipid research, glycosylation has not been widely explored at the proteome level. Techniques for analyzing complex glycoproteomes are limited. Glycoproteins differ not only in the number and location of glycosyl groups, but also in the composition and structure of each glycan. Glycoproteomics is one of the most important frontiers in life sciences.

In order to overcome the technical limitations in this field, in a new study, Dr. Josef Penninger, director of the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, and his team developed mass spectrometry and algorithms to finally synthesize complex sugar structures and map them to the correct sites for the corresponding glycoprotein. Their newly developed comparative glycoproteomics platform was published online on September 20, 2017 in the journal Nature, entitled Comparative glycoproteomics of stem cells labeled new players in ricin toxicity. The first author of the paper is Dr. Jasmin Taubenschmid, IMBA researcher, and Johannes Stadlmann, IMBA proteome researcher. Their method, called SugarQb (Sugar Quantitative Biology), provides a global understanding of protein glycosylation and glycan modification in biological systems. They applied this platform to two proof-of-concept studies - the analysis of the embryonic stem cell glycoprotein group and the identification of glycoproteins necessary for the production of ricin.

Using this new SugarQb approach, these researchers first sketched the glycoproteome of mouse and human embryonic stem cells. Their findings almost doubled the number of all known glycoproteins. They also revealed a variety of new glycosylation proteins, including evolutionarily conserved sugar modifications, and species-specific sugar modifications in mouse and human stem cell pluripotency factors. Many of these glycosylated proteins are found on cell membranes and are involved in intercellular signal transduction, cellular interactions, and embryonic development.

Ricin is a highly toxic plant toxin and biological weapon. The smuggling of ricin has raised concerns about its possible use by terrorists and terrorist organizations. There are currently no antidote to ricin. So many groups (such as pharmaceutical companies, military) are interested in developing methods to treat or prevent the toxic effects of ricin. The Penninger team has just discovered that mutant cells with fucosylation defects are resistant to ricin. Fucosylation is a glycosylation process in which fucose is added. However, fucosylation targets that promote the production of ricin toxicity are unknown.

Currently, Taubenschmid and Stadlmann use the SugarQb method to obtain the glycoprotein group of these ricin-resistant cells. Glycoproteins that change in these mutant cells may play a role in their resistance. Indeed, the Penninger team found six new glycoproteins that coordinate the toxicity of ricin. Just as there are cells with defects in fucosylation, the lack of any of these glycoproteins causes the cells to produce ricin resistance. Their findings suggest that fucosylation of these new glycoproteins is essential for ricin sensitivity and provides many new therapeutic targets for drug development.

The SugarQb method is available to all scientists for free. Stadlmann said, "We hope that our platform will allow research teams around the world to explore this unknown area by identifying sugar structures and their location on the corresponding proteins." Penninger added, "Glycosylation plays an important role in many diseases, including cancer. The SugarQb method will allow scientists to uncover new biological mechanisms and disease treatment strategies. It may also be used by clinicians to identify abnormal glycoproteins as biomarkers and tracking pairs of disease. Treatment response."

Resource: Johannes Stadlmann, Jasmin Taubenschmid, Daniel Wenzel et al. Comparative glycoproteomics of stem cells identifies new players in ricin toxicity. Nature, Published online 20 September 2017, doi:10.1038/nature24015

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