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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
PubMed

Insights

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.
Keywords:
Poly ADP-ribosylationTCF-1/LEF-1Tankyrase-1Transcription factor EBWnt

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