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PARsylated 转录因子 EB（TFEB）通过与β-catenin-TCF/LEF1 形成复合物来调节一组 Wnt 靶基因的表达。

PARsylated transcription factor EB (TFEB) regulates the expression of a subset of Wnt target genes by forming a complex with β-catenin-TCF/LEF1.

机构信息

Department of Life Science, University of Seoul, Seoul, Republic of Korea.

Confocal Core Facility, Center for Medical Innovation, Seoul National University Hospital, Seoul, Republic of Korea.

出版信息

Cell Death Differ. 2021 Sep;28(9):2555-2570. doi: 10.1038/s41418-021-00770-7. Epub 2021 Mar 22.

DOI:10.1038/s41418-021-00770-7
PMID:33753903
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8408140/
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.

摘要

Wnt 信号主要通过β-catenin 转导，通过调节包含 Axin、APC 和 GSK3β 的β-catenin 降解复合物进行。转录因子 EB（TFEB）是自噬和溶酶体生物发生过程的众所周知的主调控因子。TFEB 的核定位和转录活性也受各种上游信号的调节。在这项研究中，我们发现 Wnt 信号诱导 TFEB 的核定位，并且 Wnt 靶基因的表达受 TFEB-β-catenin-TCF/LEF1 以及β-catenin-TCF/LEF1 复合物的调节。我们的生化数据显示 TFEB 是β-catenin 降解复合物的一部分，通过敲低 Axin 或 APC 破坏降解复合物会导致 TFEB 的核定位。有趣的是，RNA-seq 分析显示，约 27%的 Wnt3a 诱导基因依赖于 TFEB。然而，这些“TFEB 介导的 Wnt 靶基因”与参与自噬和溶酶体生物发生过程的 TFEB 靶基因不同。从机制上讲，我们发现 Tankyrase (TNKS) 在 Wnt ON 信号下对 TFEB 进行 PARsylation，并且核定位的 PARsylated TFEB 与β-catenin-TCF/LEF1 形成复合物，诱导“TFEB 介导的 Wnt 靶基因”。最后，我们发现在各种类型的癌症中，TFEB 介导的 Wnt 靶基因的水平与代表 Wnt 信号活性的 Axin2 的水平呈强相关性。总的来说，我们的数据表明，Wnt 信号通过形成由 PARsylated TFEB 和β-catenin-TCF/LEF1 组成的转录因子复合物，诱导一组与以前已知的由β-catenin-TCF/LEF1 复合物或 TFEB 调节的基因不同的基因的表达。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c10/8408140/2e57358a9c41/41418_2021_770_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c10/8408140/6976fffb1e73/41418_2021_770_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c10/8408140/e78d69f22647/41418_2021_770_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c10/8408140/ec428fa0ce14/41418_2021_770_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c10/8408140/55f93a2a9341/41418_2021_770_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c10/8408140/68ce7c916223/41418_2021_770_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c10/8408140/b8b5443a80dc/41418_2021_770_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c10/8408140/2e57358a9c41/41418_2021_770_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c10/8408140/6976fffb1e73/41418_2021_770_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c10/8408140/e78d69f22647/41418_2021_770_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c10/8408140/ec428fa0ce14/41418_2021_770_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c10/8408140/55f93a2a9341/41418_2021_770_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c10/8408140/68ce7c916223/41418_2021_770_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c10/8408140/b8b5443a80dc/41418_2021_770_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1c10/8408140/2e57358a9c41/41418_2021_770_Fig7_HTML.jpg

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