Intracellular Distribution of Lysosomal Sialidase Is Controlled by the Internalization Signal in Its Cytoplasmic Tail

Abstract

Sialidase (neuraminidase), encoded by the neu-1 gene in the major histocompatibility complex locus catalyzes the intralysosomal degradation of sialylated glycoconjugates. Inherited deficiency of sialidase results in sialidosis or galactosialidosis, both severe metabolic disorders associated with lysosomal storage of oligosaccharides and glycopeptides. Sialidase also plays an important role in cellular signaling and is specifically required for the production of cytokine interleukin-4 by activated T lymphocytes. In these cells, neu-1-encoded sialidase activity is increased on the cell surface, suggesting that a specific mechanism regulates sorting of this enzyme to the plasma membrane. We investigated that mechanism by first showing that sialidase contains the internalization signal found in lysosomal membrane proteins targeted to endosomes via clathrin-coated pits.

NEU1 Sialidase Expressed in Human Airway Epithelia Regulates Epidermal Growth Factor Receptor (EGFR) and MUC1 Protein Signaling

“…6). Although the mechanisms through which NEU1 might be translocated to the plasma membrane are poorly understood, it has been detected on the surface of multiple cell types (47)(48)(49). A tyrosine-containing internalization motif in the COOH terminus of NEU1, amino acids 412-415, reportedly targets the enzyme to the lysosome in COS-7 cells, human skin fibroblasts, and lymphocytes (48).…”

“…A tyrosine-containing internalization motif in the COOH terminus of NEU1, amino acids 412-415, reportedly targets the enzyme to the lysosome in COS-7 cells, human skin fibroblasts, and lymphocytes (48). Upon NEU1 Tyr-412 phosphorylation in activated lymphocytes, NEU1 is redistributed to the cell surface (48). In other studies, NEU1 was targeted to the plasma membrane of phorbol 12-myristate 13-acetate-differentiated human monocytes (47) and activated human T lymphocytes (49).…”

“…2G, panel ii, arrows). NEU1 is a lysosomal protein (20,48). To establish whether NEU1 resides within the lysosomal compartment of airway epithelia, lysosomal preparations isolated from A549 cells were processed for immunoblotting with antibodies raised against NEU1 and the lysosomal marker LAMP1 (Fig.…”

Identification and characterization of mature β-hexosaminidases associated with human placenta lysosomal membrane

“…Several recent studies revealed the presence of glycohydrolases not only in lysosomes but also at cell surface [5,18,39,40]. They stress the potential role of a remodelling of glycosphingolipids during cellular processes [6,7]. In a recent study we demonstrated that a mature form of hexosaminidase (Hex A isoenzyme) is associated to the human fibroblast PM and is catalytically active toward its natural substrate GM2 [26].…”

“…For instance, evidence for PM sialidase Neu3 activity towards gangliosides exposed to the surface of adjacent cells has been recently demonstrated by co-culture experiments [5,6]. Moreover, the presence of the lysosomal sialidase Neu1 anchored to both lysosomal and plasma membranes has been established and an important immunoregulatory role for this enzyme has been suggested [7,8]. In particular the translocation of sialidase Neu1 from lysosomes to PM has been observed during T-cell activation, where its ability to desialylate GM3 is required for IL-4 production in activated T-cells [9][10][11].…”