Mammalian Neuraminidases in Immune-Mediated Diseases: Mucins and Beyond

Abstract

Mammalian neuraminidases (NEUs), also known as sialidases, are enzymes that cleave off the terminal neuraminic, or sialic, acid resides from the carbohydrate moieties of glycolipids and glycoproteins. A rapidly growing body of literature indicates that in addition to their metabolic functions, NEUs also regulate the activity of their glycoprotein targets. The simple post-translational modification of NEU protein targets—removal of the highly electronegative sialic acid—affects protein folding, alters protein interactions with their ligands, and exposes or covers proteolytic sites. Through such effects, NEUs regulate the downstream processes in which their glycoprotein targets participate. A major target of desialylation by NEUs are mucins (MUCs), and such post-translational modification contributes to regulation of disease processes. In this review, we focus on the regulatory roles of NEU-modified MUCs as coordinators of disease pathogenesis in fibrotic, inflammatory, infectious, and autoimmune diseases. Special attention is placed on the most abundant and best studied NEU1, and its recently discovered important target, mucin-1 (MUC1). The role of the NEU1 - MUC1 axis in disease pathogenesis is discussed, along with regulatory contributions from other MUCs and other pathophysiologically important NEU targets.

Neuraminidase 1 promotes renal fibrosis development in male mice

“…Fourth, we also reported that neuraminidases activation resulted in accumulation of circulating N -acetyl-neuraminic acid, a signaling metabolite that can trigger RhoA and Cdc42-dependent myocardial injury 21 . On account of their various functions, mammalian neuraminidases have been shown to play an emerging role in several human diseases, including autoimmune 22 , 23 , cardiovascular diseases 20 , 24 , 25 cancers 26 , neurodegenerative disorders 27 , and lung diseases 28 , 29 . Design of the specific inhibitors targeting neuraminidases have the potential to treat these diseases 30 , 31 .…”

Sialidase Inhibitors with Different Mechanisms

“… a ND: no data available. b Referred from ref . c Modified from ref . Abbreviations: ApoB100, Apolipoprotein B100; ATG5, Autophagy related 5; CD protein, cluster of differentiation protein; EGFR, epidermal growth factor receptor; HGF, hepatocyte growth factor; IR, insulin receptor; LAP: latency-associated peptide; MMP9, matrix metallopeptidase 9; MUC1 , mucin 1; TGF-β, transforming growth factor beta; TLR, toll-like receptor; TrkA, Tropomyosin receptor kinase A . …”

“…The main reason for the poor characterization the mammalian sialidases could be due to their membrane-bound structure . More detailed information on the subcellular distribution, substrate specificity, catalytic properties, and amino acid homologies of the four mammalian sialidases can be found in recent review articles. − ,,− Despite the accumulating data, molecular mechanisms underlying mammalian sialidases involvement in cellular phenomena have yet to be fully elucidated.…”

“…Overall, sialidases catalyze the cleavage of terminal Sias (desialylation), which modulate the functionality of the Sia-containing molecules, and thus are often involved in physiological and pathological processes. Imbalance in the sialidase activity could cause diseases such as cancer, diabetes, heart disease, or neurodegenerative disorders. , Therefore, sialidases could serve as potential therapeutic targets. Suitable sialidase inhibitors could be used as effective drugs for these diseases depending on which sialidase needs to be inhibited …”

“…Imbalance in the sialidase activity could cause diseases such as cancer, diabetes, heart disease, or neurodegenerative disorders. 7 , 92 Therefore, sialidases could serve as potential therapeutic targets. Suitable sialidase inhibitors could be used as effective drugs for these diseases depending on which sialidase needs to be inhibited.…”