坦基拉酶-1介导的PARsylation指导TFEB合作伙伴切换以调节选择性的Wnt目标基因表达
Gahyeon Song1, Chanhyeok Park2, Eek-Hoon Jho1
1Department of Life Science, University of Seoul, Seoul, Republic of Korea.
Molecules and cells
|January 10, 2026
概括
Wnt信号重新编程转录因子TFEB.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
背景情况:
- Wnt/β-catenin信号调节在发育和癌症中的基因表达.
- TFEB是溶酶体生物发生和自的主调节者,对一些Wnt标基因起到Wnt可诱导的共同调节作用.
- 此前,TFEB选择性参与Wnt信号的机制尚不清楚.
研究的目的:
- 阐明Wnt信号调节TFEB的转录活动的分子机制.
- 研究TFEB如何选择性地与Wnt目标基因相互作用.
主要方法:
- 在Wnt3a刺激时研究了TFEB和TCF-1/LEF-1之间的相互作用.
- 使用的TFEB突变体缺乏基本螺旋环螺旋 (bHLH) 和氨酸拉链 (LZ) 领域.
- 研究了TFEB的坦基拉酶-1 (TNKS1) 介导的PARsylation.
- 评估了PARsylation缺陷TFEB突变对Wnt-TFEB目标基因表达的影响.
主要成果:
- 刺激Wnt3a促进TFEB与TCF-1/LEF-1的相互作用,需要TFEB的bHLH和LZ域.
- Wnt信号减少了TFEB的同质化,并通过TNKS1通过bHLH域内特定的lysine残留物 (K237,K274) 诱导TFEB PARsylation.
- 缺乏PARsylation的TFEB突变不能结合TCF-1/LEF-1或诱导Wnt-TFEB目标基因.
结论:
- 发现了一种新的PARsylation-dependent伴侣交换机制,用于TFEB.
- Wnt信号重新编程TFEB的转录输出通过改变它的结合偏好从同位体到TCF-1/LEF-1复合体.
- 这种机制突出了Wnt介导的转录控制中的新层监管.
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