CHIP promotes Wnt signaling and regulates Arc stability by recruiting and polyubiquitinating LEF1 or Arc

Yuchun Liu,Yuming Xu,Shoutao Zhang,Yao Sun,Kang Cheng,Qingnan Tian,Yonghui Huang

doi:10.1038/s41420-020-00394-9

Abstract

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.

Highlights

The carboxy-terminus of HSC70-interacting protein (CHIP), encoded by the STUB1 gene, is an E3 ubiquitin ligase containing a three tetratricopeptide repeat domains, and a U-box domain displaying E3 ubiquitination ligase activity which participates in many vital processes to modulate protein degradation, cell proliferation, metastasis, and tumor progression[1]
carboxyl terminus of Hsc70-interacting protein (CHIP) promotes the activation of Wnt signaling and the degradation of Arc Recent studies have reported that CHIP (p.T246M)
We confirmed that Wnt signaling was inhibited in the rat model of spinocerebellar autosomal recessive 16 (SCAR16) induced by CHIP T246M mutant, suggesting that CHIP mutant might trigger SCAR16 by attenuating the activation of Wnt signaling (Fig. 1I)

Summary

Introduction

The carboxy-terminus of HSC70-interacting protein (CHIP), encoded by the STUB1 gene, is an E3 ubiquitin ligase containing a three tetratricopeptide repeat domains, and a U-box domain displaying E3 ubiquitination ligase activity which participates in many vital processes to modulate protein degradation, cell proliferation, metastasis, and tumor progression[1]. CHIP is reported to regulate the ubiquitination and degradation of RIPK3, PTEN, HIF1A, TRAF2/6, and Smad1/Smad[4] to regulate multiple signal transductions like necroptosis, autophagy, apoptosis, NF-κB pathway, and TGF-β pathway[2,3,4,5,6,7,8,9]. It interacts with Tau, Parkin, α-Synuclein, LRRK2, Ataxin[1], and Ataxin[3] which involve in the pathogenesis of various neurodegenerative diseases[10,11,12,13,14,15]. It remains to be fully elucidated of the detailed pathogenic mechanism of SCAR16 caused by CHIP (p.T246M) mutant

Methods

Results

Conclusion