Abstract
Transcription factor EB (TFEB) is a master regulator of the autophagy-lysosomal pathway (ALP). Here, we cloned a novel splicing variant of TFEB, comprising 281 amino acids (hereafter referred to as small TFEB), and lacking the helix-loop-helix (HLH) and leucine zipper (LZ) motifs present in the full-length TFEB (TFEB-L). The TFEB variant is widely expressed in several tissues, including the brain, although its expression level is considerably lower than that of TFEB-L. Intriguingly, in cells stably expressing small TFEB, the expression profile of genes was inverted compared to that in cells ectopically expressing TFEB-L. In addition, fisetin-induced luciferase activity of promoter containing either coordinated lysosomal expression and regulation (CLEAR) element or antioxidant response element (ARE) was significantly repressed by co-transfection with small TFEB. Moreover, fisetin-mediated clearance of phosphorylated tau or α-synuclein was attenuated in the presence of small TFEB. Taken together, the results suggest that small TFEB is a novel splicing variant of TFEB that might act as a negative regulator of TFEB-L, thus fine tuning the activity of ALP during cellular stress.
Highlights
Autophagy is a cellular degradation process by which cytoplasmic constituents such as misfolded proteins, defective organelles, or invaded microorganisms are degraded via the lysosome[1,2]
To determine how the small Transcription factor EB (TFEB) was derived from the TFEB gene, we sequenced the small TFEB variant cloned into pHM6
To examine the expression of the small TFEB splicing variant in various tissues, we performed PCR using human cDNA panel prepared from various tissues
Summary
Autophagy is a cellular degradation process by which cytoplasmic constituents such as misfolded proteins, defective organelles, or invaded microorganisms are degraded via the lysosome[1,2]. Nuclear TFEB induces the expression of its target genes, which are involved in the autophagy-lysosomal pathway (ALP) and cellular metabolism, by binding to the coordinated lysosomal enhancement and regulation (CLEAR) elements in the respective gene p romoters[12,14]. Compelling evidence has shown that α-synuclein aggregation disrupts the retrograde transport of AVs, impairing autophagosome maturation and fusion with lysosomes[21,22]. Accumulating evidence has shown that TFEB overexpression or its pharmacological activation in cellular and mouse models of AD and PD can reduce protein aggregation and improve neurological functions[23,24,25,26,27,28], indicating that proper regulation of TFEB activity is critical for maintaining healthy neurons. We describe the molecular properties of small TFEB and its implications for neurodegenerative diseases
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