Abstract
The monocarbonyl analogue of curcumin (1E,4E)-1,5-Bis(2-methoxyphenyl)penta-1,4-dien-3-one (C1) has been used as a specific activator of the master gene transcription factor EB (TFEB) to correlate the activation of this nuclear factor with the increased activity of lysosomal glycohydrolases and their recruitment to the cell surface. The presence of active lysosomal glycohydrolases associated with the lipid microdomains has been extensively demonstrated, and their role in glycosphingolipid (GSL) remodeling in both physiological and pathological conditions, such as neurodegenerative disorders, has been suggested. Here, we demonstrate that Jurkat cell stimulation elicits TFEB nuclear translocation and an increase of both the expression of hexosaminidase subunit beta (HEXB), hexosaminidase subunit alpha (HEXA), and galactosidase beta 1 (GLB1) genes, and the recruitment of β-hexosaminidase (Hex, EC 3.2.1.52) and β-galactosidase (Gal, EC 3.2.1.23) on lipid microdomains. Treatment of Jurkat cells with the curcumin analogue C1 also resulted in an increase of both lysosomal glycohydrolase activity and their targeting to the cell surface. Similar effects of C1 on lysosomal glycohydrolase expression and their recruitment to lipid microdomains was observed by treating the SH-SY5Y neuroblastoma cell line; the effects of C1 treatment were abolished by TFEB silencing. Together, these results clearly demonstrate the existence of a direct link between TFEB nuclear translocation and the transport of Hex and Gal from lysosomes to the plasma membrane.
Highlights
Transcription factor EB (TFEB) is a master regulator of many cellular processes, such as lysosomal functions, autophagy, and membrane repair [1,2,3,4]
It has been shown that TFEB nuclear translocation
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Summary
Transcription factor EB (TFEB) is a master regulator of many cellular processes, such as lysosomal functions, autophagy, and membrane repair [1,2,3,4]. TFEB recognizes and binds to a regulatory sequence, the coordinated lysosomal expression and regulation (CLEAR) motif, which is present in the promoter region of several lysosomal genes [8]. TFEB modulates and coordinates the main lysosome-dependent degradative pathways to promote intracellular clearance. Numerous studies support the idea that impaired TFEB function may contribute to the pathogenesis of most degenerative diseases characterized by aberrant intracellular accumulation of macromolecules [11,12,13]. Genetic or pharmacological activation of TFEB proved to be beneficial in a variety of neurodegenerative and lysosomal storage diseases (LSDs) [14,15,16]
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