Deciphering the role of membrane sialidase NEU1 in macrophages – MACRONEU1

Sialidases, or neuraminidases, represent a family of exoglycosidases removing terminal sialic acid residues from glycoproteins, glycolipids and oligosaccharides. Their presence affects the molecular properties and structure of glycoconjugates, modifying their function and interactions with other molecules. Therefore, the sialylation state of glycoproteins and glycolipids has been recognized as a critical factor modulating molecular recognitions inside the cell, between the cells, and between the cells and the extracellular matrix. The human sialidase family contains four members: the lysosomal NEU1, cytosolic NEU2, and membrane-bound NEU3 and NEU4. Recent data from the literature shows that, in addition to lysosomes, NEU1 can be present at the plasma membrane of several cell types. At the plasma membrane, NEU1 is required for signal transduction and elastogenesis through the elastin receptor complex but is also involved in the regulation and function of several membrane receptors by desialylation and in receptor transactivation. Consequently, NEU1 now emerges not only as a catabolic enzyme but also as a key actor involved in cell signaling regulation.
Despite a growing interest of the scientific community to NEU1, notably because NEU1 is the target of oseltamivir phosphate, the widely used anti-influenza sialidase inhibitor Tamiflu, little is known about the role of NEU1 in macrophages, critical players of atherosclerosis. Atherosclerosis is at the basis of most of cardiovascular diseases (CVD), the main cause of death in the world, and represents a major problem of public health. Indeed, incidence of CVD is increasing with the growing aging of the population and generates abysmal direct and indirect costs for France, European Union, and all developed countries. Therefore, better understanding of the molecular and cellular mechanisms involved in atherosclerosis is crucial to identify potential targets for new innovative medicines in order to improve the citizen quality of life and reduce the financial and societal impacts of these diseases.
Using a combination of participants internationally recognized in their respective field, this 3 years' MACRONEU1 project aims at deciphering the role played by NEU1 in macrophages, crucial actors of atherosclerosis, by two original ways. First, the interacting partners of membrane NEU1 in human macrophages will be identified and characterized from two complementary approaches: tandem affinity purification and split-ubiquitin yeast two-hybrid. A first set of potential candidates is already available and the functional characterization of thee relevant membrane interacting partners of NEU1 is already proposed in this project: CD36, TLR and Galphai2 proteins. The second part of the project is based on recent published data from the Scientific coordinator's lab demonstrating, for the first time, that NEU1 harbors a dimerization interface involved in its membrane dimerization and sialidase activity (Maurice et al, Sci Rep. 2016). We therefore propose the development of two complementary interfering peptide strategies aiming at disrupting NEU1 dimerization and affecting its sialidase activity. Effects of these promising tools will then be evaluated, in parallel to the use of the broad-spectrum sialidase inhibitor Tamiflu, in two animal models of atherosclerosis to determine if NEU1 may constitute a pharmacological target to reduce atherosclerosis progression.
Together, this ambitious and innovative MACRONEU1 project will undoubtedly bring crucial information on the role played by this sialidase in the main macrophage functions during atherosclerosis and propose an innovative strategy of high-added value to target NEU1 in vivo and to evaluate its therapeutic potential on atherosclerosis. Importantly, the contribution of NEU1 in atherosclerosis development and the use of the anti-influenza sialidase inhibitor Tamiflu in atherosclerosis have never been considered so far.