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Molecular Neurobiology

, Volume 55, Issue 5, pp 3812–3821 | Cite as

UCH-L1 Inhibition Suppresses tau Aggresome Formation during Proteasomal Impairment

  • Quntao Yu
  • Hongmao Zhang
  • Yuan Li
  • Chao Liu
  • Shaohui Wang
  • Xiaomei Liao
Article

Abstract

In conditions of proteasomal impairment, the damaged or misfolded proteins, collectively known as aggresome, can accumulate in the perinuclear space and be subsequently eliminated by autophagy. Abnormal aggregation of microtubule-associated protein tau in the cytoplasm is a common neuropathological feature of tauopathies. The deficiency in ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a proteasomal deubiquitinating enzyme, is closely related to tau aggregation; however, the associated mechanisms remain unclear. Here, we showed that UCH-L1 inhibition interrupts proteasomal impairment-induced tau aggresome formation. By reducing the production of lysine (K63)-linked ubiquitin chains, UCH-L1 inhibition decreases HDAC6 deacetylase activity and attenuates the interaction of HDAC6 and tau protein, finally leading to tau aggresome formation impairment. All these results indicated that UCH-L1 plays a key role in the process of tau aggresome formation by regulating HDAC6 deacetylase activity and implied that UCH-L1 may act as a signaling molecule to coordinate the effects of the ubiquitin-proteasome system and the autophagy-lysosome pathway, which mediate protein aggregates degradation in the cytoplasm.

Keywords

Ubiquitin carboxy-terminal hydrolase L1 Tau aggresome K63-linked ubiquitin chains Histone deacetylase 6 

Notes

Acknowledgements

We thank Professor Wang Jianzhi at the Tongji Medical College of Huazhong University of Sciences and Technology, Wuhan, China for providing the HEK293/tau441 cell line used in this study. This work was financially supported by the Nature Science foundation of Hubei Province (No. 2016CFB561), the project of Hubei Key Laboratory of Genetic Regulation and Integrative Biology (Grant No. GRIB201604), and the National Natural Science Foundation of China (No. 31372212).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2017_558_MOESM1_ESM.doc (68 kb)
ESM 1 (DOC 68 kb)

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.School of Life Sciences, Hubei Key Lab of Genetic Regulation and Integrative BiologyCentral China Normal UniversityWuhanPeople’s Republic of China

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