Where catabolism meets signalling: neuraminidase 1 as a modulator of cell receptors

Abstract

Terminal sialic acid residues are found in abundance in glycan chains of glycoproteins and glycolipids on the surface of all live cells forming an outer layer of the cell originally known as glycocalyx. Their presence affects the molecular properties and structure of glycoconjugates, modifying their function and interactions with other molecules. Consequently, the sialylation state of glycoproteins and glycolipids has been recognized as a critical factor modulating molecular recognitions inside the cell, between the cells, between the cells and the extracellular matrix, and between the cells and certain exogenous pathogens. Sialyltransferases that attach sialic acid residues to the glycan chains in the process of their initial synthesis were thought to be mainly responsible for the creation and maintenance of a temporal and spatial diversity of sialylated moieties. However, the growing evidence also suggests that in mammalian cells, at least equally important roles belong to sialidases/neuraminidases, which are located on the cell surface and in intracellular compartments, and may either initiate the catabolism of sialoglycoconjugates or just cleave their sialic acid residues, and thereby contribute to temporal changes in their structure and functions. The current review summarizes emerging data demonstrating that neuraminidase 1 (NEU1), well known for its lysosomal catabolic function, can be also targeted to the cell surface and assume the previously unrecognized role as a structural and functional modulator of cellular receptors.

Structural Basis for Substrate Specificity of Mammalian Neuraminidases

“…Our current data show that Neu1 is capable of cleaving Sia residues from glycans containing both GlcNAc and Glc in the third position, and present in di-sialo and mono-sialo gangliosides, respectively. Besides catabolism, Neu1 has important regulatory functions, such as desialylation of multiple surface receptors in immune, metabolic, and cell proliferation pathways [reviewed in [67]]. The broad specificity of Neu1 we report here helps to explain the enzyme's ability to act on a wide range of receptors with diverse structures of the glycan chains.…”

Characterizing the genetic basis of innate immune response in TLR4-activated human monocytes

“…For example, NEU1-the best-characterized neuraminidase-promotes the cleavage of sialic acids from the ectodomain of TLR4, which is a prerequisite for TLR activation 11 . Although a similar effect on TLR4 has been observed for NEU4 (ref.…”

New Insights into Molecular Organization of Human Neuraminidase-1: Transmembrane Topology and Dimerization Ability

“…At the plasma membrane, NEU1 has been shown to be required for signal transduction and elastogenesis through the elastin receptor complex91011 and to be involved in the modulation of insulin receptor signaling1213, regulation of integrin beta 414, TLR415, Trk A16, PDGF-BB and IGF receptors17, EGF and MUC1 receptors18 and more recently CD3119. Consequently, NEU1 now emerges not only as a catabolic enzyme but also as a key actor involved in cell signaling regulation20. Despite a growing interest of the scientific community to NEU1, its organization and dynamics in membrane are not understood.…”