TFEB overexpression promotes the translocation of lysosomal glycohydrolases beta-hexosaminidase and beta-galactosidase to cell surface lipid microdomains

The lysosomes are membrane-enclosed organelles, containing acid hydrolase enzymes, that mediate a variety of physiological processes, such as macromolecule degradation, lipid homeostasis, energy metabolism and pathogen defence. Recently, it has been demonstrated that adaptive response of the lysosomes to physiologic signals is related to the activity of the transcription factor EB (TFEB). TFEB overexpression induces autophagy, lysosome biogenesis, up-regulation of lysosomal genes expression, and leads to clearance of storage material in several lysosomal storage disorder cell models by promoting lysosomal exocytosis [1], which is in turn responsible for the secretion of lysosomal content in extracellular environment and repair of plasma membrane (PM). In a recent work, in which the association of fully processed glycohydrolases b-hexosaminidase (Hex) and b-galactosidase (Gal) to PM lipid microdomains has been provided [2], we speculated on the existence of a lysosome-to-PM transport pathway mediating the translocation of lysosomal membrane-associated enzymes to the cell surface [2,3,4]. To test this hypothesis we transfected Hek 293 cells by using a TFEB expressing vector. Stable TFEB overexpression significantly increased lysosomal Hex and Gal activities and triggered their recruitment on cell surface lipid microdomains. Taken together these observations suggest that up-regulation of the lysosomal system due to TFEB over-expression is mirrored by a lysosomal glycohydrolases recruitment to the PM, where they may be involved in glycosphingolipids oligosaccharide modification processes regulating cell-to-cell and/or cell environment interactions in both physiological and pathological conditions.