Wang Yuting, Yue Jicheng, Xiao Mingzhe, Lu Xiaomei, Chin Yuen Eugene
Institutes of Biology and Medical Sciences, Soochow University School of Medicine, Suzhou, China.
The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China.
Front Oncol. 2022 May 30;12:872444. doi: 10.3389/fonc.2022.872444. eCollection 2022.
Axin1 is a fundamental scaffolding protein of the destruction complex in the canonical Wnt signaling pathway, which plays a critical role in various biological processes. However, how Axin1 is regulated in the activation of the canonical Wnt signaling pathway remains elusive. Here, we report that Axin1 is constitutively acetylated in resting cells. Upon stimulation with Wnt, SIRT4 translocates from mitochondria to the cytoplasm and catalyzes Axin1 deacetylation, thus turning off the destruction complex. In this process, Lys147, a residue in the RGS domain of Axin1, plays a key role. We proved that the Axin1-K147R mutant impairs the assembly of β-TrCP to the destruction complex, which leads to β-catenin accumulation even without Wnt stimulation. In summary, our work proposes a new model for better understanding the initial stage of the canonical Wnt signaling pathway in which SIRT4 translocates from mitochondria into the cytoplasm to deacetylate Axin1-K147 after Wnt stimulation, which results in reduced assembly of β-TrCP to the destruction complex.
Axin1是经典Wnt信号通路中破坏复合物的一种基本支架蛋白，在各种生物学过程中起关键作用。然而，Axin1在经典Wnt信号通路激活过程中是如何被调控的仍不清楚。在此，我们报告Axin1在静息细胞中持续发生乙酰化。在Wnt刺激后，SIRT4从线粒体转移到细胞质并催化Axin1去乙酰化，从而关闭破坏复合物。在此过程中，Axin1的RGS结构域中的一个残基Lys147起关键作用。我们证明Axin1-K147R突变体损害β-TrCP与破坏复合物的组装，这导致即使在没有Wnt刺激的情况下β-连环蛋白也会积累。总之，我们的工作提出了一个新模型，以更好地理解经典Wnt信号通路的初始阶段，即在Wnt刺激后，SIRT4从线粒体转移到细胞质中使Axin1-K147去乙酰化，这导致β-TrCP与破坏复合物的组装减少。
