Liu Yuchun, Sun Yao, Huang Yonghui, Cheng Kang, Xu Yuming, Tian Qingnan, Zhang Shoutao
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
School of LifeSciences, Zhengzhou University, Zhengzhou, Henan, China.
Cell Death Discov. 2021 Jan 11;7(1):5. doi: 10.1038/s41420-020-00394-9.
The carboxyl terminus of Hsc70-interacting protein (CHIP), an E3 ubiquitin ligase, participates in many cellular processes such as protein degradation, trafficking, autophagy, apoptosis, and multiple signaling transductions. The mutant of CHIP (p.T246M) causes the spinocerebellar autosomal recessive 16 (SCAR16), a neurodegenerative disease characterized by spinocerebellar atrophy. Previous studies have shown that Wnt signaling and activity-regulated cytoskeleton-associated protein (Arc) play important roles in neurodegenerative diseases. However, the mechanisms by which CHIP regulates Wnt signaling and the stability of Arc that may affect SCAR16 are still unclear. We show that overexpression of CHIP promoted the activation of Wnt signaling, and enhanced the interaction between LEF1 and β-catenin through heightening the K63-linked polyubiquitin chains attached to LEF1, while the knockdown of CHIP had the opposite effect. Moreover, we verified that Wnt signaling was inhibited in the rat models of SCAR16 induced by the CHIP (p.T246M) mutant. CHIP also accelerated the degradation of Arc and regulated the interaction between Arc and GSK3β by heightening the K48- or K63-linked polyubiquitin chains, which further potentiated the interaction between GSK3β and β-catenin. Our data identify that CHIP is an undescribed regulator of Wnt signaling and Arc stability which may be related to the occurrence of SCAR16.
热休克蛋白 70 相互作用蛋白（CHIP）的羧基末端是一种 E3 泛素连接酶，参与蛋白质降解、运输、自噬、凋亡和多种信号转导等许多细胞过程。CHIP 的突变体（p.T246M）会导致常染色体隐性遗传性脊髓小脑共济失调 16 型（SCAR16），这是一种以脊髓小脑萎缩为特征的神经退行性疾病。先前的研究表明，Wnt 信号通路和活性调节细胞骨架相关蛋白（Arc）在神经退行性疾病中起重要作用。然而，CHIP 调节 Wnt 信号通路以及可能影响 SCAR16 的 Arc 稳定性的机制仍不清楚。我们发现，CHIP 的过表达促进了 Wnt 信号通路的激活，并通过增加与 LEF1 相连的 K63 连接的多聚泛素链增强了 LEF1 与 β-连环蛋白之间的相互作用，而敲低 CHIP 则产生相反的效果。此外，我们证实，在由 CHIP（p.T246M）突变体诱导的 SCAR16 大鼠模型中，Wnt 信号通路受到抑制。CHIP 还通过增加 K48 或 K63 连接的多聚泛素链加速了 Arc 的降解，并调节了 Arc 与 GSK3β 之间的相互作用，这进一步增强了 GSK3β 与 β-连环蛋白之间的相互作用。我们的数据表明，CHIP 是 Wnt 信号通路和 Arc 稳定性的一种未被描述的调节因子，这可能与 SCAR16 的发生有关。
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