A splicing variant of TFEB negatively regulates the TFEB-autophagy pathway

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...

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Bibliographic Details
Published in:Scientific reports 2021-10, Vol.11 (1), p.21119-21119, Article 21119
Main Authors: Park, Jee-Yun, Sohn, Hee-Young, Koh, Young Ho, Jo, Chulman
Format: Article
Language:English
Subjects:
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Alternative Splicing
Amino acids
Animals
Antioxidants
Autophagy
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism
Cell Line, Tumor
Cellular stress response
Gene expression
HEK293 Cells
Helix-loop-helix
Humanities and Social Sciences
Humans
Leucine zipper proteins
Mice
multidisciplinary
Phagocytosis
Protein Isoforms - genetics
Protein Isoforms - metabolism
Rats
Science
Science (multidisciplinary)
Signal Transduction
Splicing
Synuclein
Transfection
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Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-021-00613-y