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Exploring Sequence Space to Identify Binding Sites for Regulatory RNA-Binding Proteins
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Tankyrase-1-mediated PARsylation directs TFEB partner switching to regulate selective Wnt target gene expression
Gahyeon Song1, Chanhyeok Park2, Eek-Hoon Jho1
1Department of Life Science, University of Seoul, Seoul, Republic of Korea.
Molecules and Cells
|January 10, 2026
Summary
Wnt signaling reprograms transcription factor TFEB
Area of Science:
- Cellular Biology
- Molecular Biology
- Genetics
Background:
- Wnt/β-catenin signaling regulates gene expression in development and cancer.
- TFEB, a master regulator of lysosomal biogenesis and autophagy, acts as a Wnt-inducible co-regulator for some Wnt target genes.
- The mechanism for TFEB's selective engagement in Wnt signaling was previously unclear.
Purpose of the Study:
- To elucidate the molecular mechanism by which Wnt signaling modulates TFEB's transcriptional activity.
- To investigate how TFEB selectively interacts with Wnt target genes.
Main Methods:
- Studied the interaction between TFEB and TCF-1/LEF-1 upon Wnt3a stimulation.
- Utilized TFEB mutants deficient in basic helix-loop-helix (bHLH) and leucine zipper (LZ) domains.
- Investigated Tankyrase-1 (TNKS1)-mediated PARsylation of TFEB.
- Assessed the impact of PARsylation-deficient TFEB mutants on Wnt-TFEB target gene expression.
Main Results:
- Wnt3a stimulation promotes TFEB interaction with TCF-1/LEF-1, requiring TFEB's bHLH and LZ domains.
- Wnt signaling reduces TFEB homodimerization and induces TFEB PARsylation at specific lysine residues (K237, K274) within the bHLH domain via TNKS1.
- PARsylation-deficient TFEB mutants cannot bind TCF-1/LEF-1 or induce Wnt-TFEB target genes.
Conclusions:
- Uncovered a novel PARsylation-dependent partner-switching mechanism for TFEB.
- Wnt signaling reprograms TFEB's transcriptional output by altering its binding preference from homodimers to TCF-1/LEF-1 complexes.
- This mechanism highlights a new layer of regulation in Wnt-mediated transcriptional control.
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