Intracellular distribution of lysosomal sialidase is controlled by the internalization signal in its cytoplasmic tail

Sialidase (neuraminidase), encoded by the neu-1 gene in the major histocomp atibility complex locus catalyzes the intralysosomal degradation of sialyla ted glycoconjugates. Inherited deficiency of sialidase results in sialidosi s or galactosialidosis, both severe metabolic disorders associated with lys osomal storage of oligosaccharides and glycopeptides. Sialidase also plays an important role in cellular signaling and is specifically required for th e 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 th e plasma membrane. We investigated that mechanism by first showing that sia lidase contains the internalization signal found in lysosomal membrane prot eins targeted to endosomes via clathrin-coated pits. The signal consists of a C-terminal tetrapeptide (412)YGTL(415), with Tyr(412) and Leu(415) essen tial for endocytosis of the enzyme. We further demonstrated that redistribu tion of sialidase from lysosomes to the cell surface of activated lymphocyt es is accompanied by increased reactivity of the enzyme with anti-phosphoty rosine antibodies. We speculate that phosphorylation of Tyr(412) results in inhibition of sialidase internalization in activated lymphocytes.