Neuraminidase-1 is required for the normal assembly of elastic fibers

Abstract

The assembly of elastic fibers in tissues that undergo repeated cycles of extension and recoil, such as the lungs and blood vessels, is dependent on the proper interaction and alignment of tropoelastin with a microfibrillar scaffold. Here, we describe in vivo histopathological effects of neuraminidase-1 (Neu1) deficiency on elastin assembly in the lungs and aorta of mice. These mice exhibited a tight-skin phenotype very similar to the Tsk mouse. Normal septation of Neu1-null mice did not occur in neonatal mice, resulting in enlarged alveoli that were maintained in adults. The abnormal development of elastic fibers was remarkable under electron microscopy and confirmed by the overlapping distribution of elastin, fibrillin-1, fibrillin-2, and fibulin-5 (Fib-5) by the light microscopy immunostainings. Fib-5 fibers appeared diffuse and unorganized around the alveolar walls and the apex of developing secondary septal crests. Fibrillin-2 deposition was also abnormal in neonatal and adult lungs. Dispersion of myofibroblasts appeared abnormal in developing lungs of Neu1-null mice, with a random distribution of myofibroblast around the alveolar walls, rather than concentrating at sites of elastin synthesis. The elastic lamellae in the aorta of the Neu1-null mice were thinner and separated by hypertrophic smooth muscle cells that were surrounded by an excess of the sialic acid-containing moieties. The concentration of elastin, as measure by desmosine levels, was significantly reduced in the aorta of Neu1-null mice. Message levels for tropoelastin and Fib-5 were normal, suggesting the elastic fiber defects in Neu1-null mice result from impaired extracellular assembly. elastin; fibulin-5; fibrillin; extracellular matrix ELASTIN IS SYNTHESIZED in the cell as a soluble precursor, tropoelastin, which is transported to the cell surface bound to the 67-kDa elastin-binding protein, EBP, a recyclable molecular chaperone that facilitates the secretion of tropoelastin (6,31,32). EBP is an enzymatically inactive splice variant of lysosomal ␤-galactosidase (␤-Gal) and was originally named short ␤-Gal (S-Gal) (31). The orderly release of tropoelastin into the extracellular matrix occurs at the cell surface, where the tropoelastin is then assembled onto a scaffold of microfibrils and cross-linked by lysyl oxidase into mature elastic fibers. These elastic fibers are composed of two major components: a core containing resilient polymer elastin and 10-to 12-nm microfibrils made up of several structural glycoproteins; fibrillins (FBN) 1, 2, and 3, fibulins 1, 3, and 5 (Fib-5), and MAGP (8,

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

“…Similarly, the NEU1-deficient fibroblasts from sialidosis patients have impaired elastogenesis, which could be reversed after the transfection of cells with vectors containing NEU1 and CathA cDNA [110]. Impaired elastogenesis connected to the defective development of aorta, skin and lungs has also been detected in NEU1 KO mice [116]. In particular, the elastic lamellae in the aorta of the NEU1 KO mice were thinner and separated by hypertrophic smooth muscle cells that were surrounded by an excess of the sialic acidcontaining moieties.…”

“…In particular, the elastic lamellae in the aorta of the NEU1 KO mice were thinner and separated by hypertrophic smooth muscle cells that were surrounded by an excess of the sialic acidcontaining moieties. The concentration of elastin in the aorta was significantly reduced but the production of tropoelastin was normal, suggesting the elastic fiber defects result from impaired extracellular assembly [116]. Altogether, the reviewed data implicate NEU1 and the important functional component of the elastin receptor contributing to the normal development of elastic fibers, a crucial component of the cardiovascular and respiratory systems.…”

Dependence of pathogen molecule-induced Toll-like receptor activation and cell function on Neu1 sialidase

“…They are lysosomal Neu1 [18,[23][24][25][26][27][28], cytosolic Neu2 and the plasma membrane bound Neu3 [29][30][31]. The fourth sialidase Neu4 is localized to either the mitochondrial [32] compartment or the lysosomal lumen [33].…”

Thymoquinone from nutraceutical black cumin oil activates Neu4 sialidase in live macrophage, dendritic, and normal and type I sialidosis human fibroblast cells via GPCR Gαi proteins and matrix metalloproteinase-9

“…They are lysosomal Neu1 [21][22][23][24][25][26][27], cytosolic Neu2 and the plasma membrane bound Neu3 [28][29][30]. The fourth sialidase Neu4 is localized to either the mitochondrial [31] compartment or the lysosomal lumen [32].…”