Abstract
Wnt signaling is mainly transduced by β-catenin via regulation of the β-catenin destruction complex containing Axin, APC, and GSK3β. Transcription factor EB (TFEB) is a well-known master regulator of autophagy and lysosomal biogenesis processes. TFEB’s nuclear localization and transcriptional activity are also regulated by various upstream signals. In this study, we found that Wnt signaling induces the nuclear localization of TFEB and the expression of Wnt target genes is regulated by TFEB-β-catenin-TCF/LEF1 as well as β-catenin-TCF/LEF1 complexes. Our biochemical data revealed that TFEB is a part of the β-catenin destruction complex, and destabilization of the destruction complex by knockdown of either Axin or APC causes nuclear localization of TFEB. Interestingly, RNA-sequencing analysis revealed that about 27% of Wnt3a-induced genes were TFEB dependent. However, these “TFEB mediated Wnt target genes” were different from TFEB target genes involved in autophagy and lysosomal biogenesis processes. Mechanistically, we found that Tankyrase (TNKS) PARsylates TFEB with Wnt ON signaling, and the nuclear localized PARsylated TFEB forms a complex with β-catenin-TCF/LEF1 to induce the “TFEB mediated Wnt target genes”. Finally, we found that in various types of cancer, the levels of TFEB mediated Wnt target genes exhibit strong correlations with the level of Axin2, which represents the activity of Wnt signaling. Overall, our data suggest that Wnt signaling induces the expression of a subset of genes that are distinct from previously known genes regulated by the β-catenin-TCF/LEF1 complex or TFEB, by forming a transcription factor complex consisting of PARsylated TFEB and β-catenin-TCF/LEF1.
Highlights
The findings presented here demonstrate that Transcription factor EB (TFEB), which is known as a master regulator of genes related to lysosomal biogenesis, is a novel terminal regulator of Wnt/β-catenin signaling
Since Wnt signaling suppresses GSK3β [32], known to control nuclear localization of TFEB, we initially postulated that Wnt signaling may regulate autophagy; it turned out that nuclear-localized TFEB due to activation of Wnt did not induce expression of the genes involved in lysosomal biogenesis
TNKS, activated by Wnt signaling by yet an unknown mechanism, PARsylates TFEB and dissociates TFEB from the β-catenin destruction complex, which leads to nuclear localization of TFEB in the Wnt ON situation
Summary
Wnt/β-catenin mediated gene expression is controlled by the transcription co-activator β-catenin. GSK3β phosphorylates numerous substrates besides β-catenin and recent research suggests that inhibition of GSK3β by Wnt signaling stabilizes multiple proteins including c-MYC with the resultant control of biological processes such as cell division by Wnt [10,11,12,13]. We showed that TFEB, a master regulator of expression of genes related to lysosomal biogenesis, acts as a novel mediator of Wnt signaling cascade. Nuclear TFEB induced by Wnt signaling did not induce lysosomal gene expression. We found that TNKS1, a poly ADP-ribosylating enzyme, PARsylates TFEB upon Wnt treatment in turn induced nuclear localization TFEB and expression of TFEBmediated Wnt target genes. The PARsylated TFEB was bound to TCF/LEF1-β-catenin, explaining the different profile of TFEB-mediated Wnt target genes from the profile of genes induced by TCF/LEF1-β-catenin or the starvation mediated TFEB
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