Protein glycosylation in development, physiology and disease: Revealing functional mechanisms using Drosophila model
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abstract
Our project investigates fundamental biological principles of protein glycosylation that operate in insects and vertebrate animals. These principles include both evolutionarily conserved mechanisms, as well as species-specific cellular and molecular processes that operate differently in plants, insects and vertebrate animals. Revealing these mechanisms will allow to design new compounds and protocols to specifically affect insect but not mammalian or plant physiology, or environment, thus providing important tools to control invertebrate pests and parasites of agriculturally important plants and animals. The pathways that we study are involved in stress responses and maintenance of muscle health, and thus our research can suggest dietary, genetic, behavioral and environmental approaches that can improve husbandry practices, production and resistance of agricultural species to stress conditions. Finally, our research is expected to suggest ways to manage neurological conditions, such as stress and fatigue, which should help farmers and ranchers to withstand various stresses associated with their profession.The majority of proteins in animal cells are glycosylated. Glycan modifications represent the most abundant and structurally complex posttranslational modifications of proteins. These modifications have numerous important functions in animal organisms, regulating growth, differentiation, and morphogenesis during development. They play key roles in cell signaling and adhesion during normal physiological processes, while also profoundly affecting pathophysiological conditions. O-mannosylation and sialylation are among particular important type of protein glycosylation. These types of glycosylation are crucially important for the nervous system and muscle functions. Defects in these pathways are associated with severe disorders, such as muscular dystrophies and various neurological abnormalities, including epilepsy and intellectual disabilities. Despite recent progress in structural and biochemical characterization of glycans and enzymes of these pathways, the in vivo mechanisms of glycan functions and the regulation of corresponding glycosylation pathways remain poorly understood. This knowledge gap is explained by the intricacies of mammalian glycosylation, increased redundancy and pleiotropy of glycosylation genes, along with limitations of available in vivo approaches. To overcome these roadblocks, it is instrumental to develop relevant models and carry our studies using genetically amenable systems such as Drosophila. Our previous research, as well as studies of other scientists, revealed functions and mechanisms of O-linked glycosylation, including glycosylation-mediated regulation of Notch signaling that controls development of a wide range of organisms, from sea urchins to humans [1, 2]. Studies in Drosophila shed light on the function of O-mannosylation in regulation of Dystroglycan pathway that is essential for muscle development and physiology [3, 4]. Yet another example of an important glycosylation pathway is sialylation that plays critical role in the nervous system [5-7].........."
