HSP90 recognizes the N-terminus of huntingtin involved in regulation of huntingtin aggregation by USP19

Wen Tian He, Wei Xue, Yong Guang Gao, Jun Ye Hong, Hong Wei Yue, Lei Lei Jiang, Hong Yu Hu

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33 Scopus citations

Abstract

Huntington's disease (HD) is caused by aberrant expansion of polyglutamine (polyQ) in the N-terminus of huntingtin (Htt). Our previous study has demonstrated that HSP90 is involved in the triage decision of Htt, but how HSP90 recognizes and regulates Htt remains elusive. We investigated the interaction between HSP90 and the N-terminal fragments of Htt (Htt-N), such as the N-terminal 90-residue fragment (Htt-N90). Our results showed that HSP90 binds to the N-terminal extreme of Htt-N in a sequence just ahead of the polyQ tract. Structural integration of the middle and C-terminal domains of HSP90 is essential for interacting with Htt-N90, and the dimerization mediated by the C-terminal domain facilitates this interaction. Moreover, ubiquitin-specific protease 19 (USP19), a deubiquitinating enzyme interacting with HSP90, up-regulates the protein level of Htt-N90 and consequently promotes its aggregation, whereas disruption of the interaction between Htt-N90 and HSP90 attenuates the effect of USP19 on Htt-N90. Thus, HSP90 interacts with Htt-N90 on the N-terminal amphipathic α-helix, and then recruits USP19 to modulate the protein level and aggregation of Htt-N90. This study provides mechanistic insights into the recognition between HSP90 and the N-terminus of Htt, and the triage decision for the Htt protein by the HSP90 chaperone system.

Original languageEnglish (US)
Article number14797
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

Bibliographical note

Funding Information:
The authors thank Dr. Zheng-Hong Qin, Suchow University for providing Htt-N552 plasmid and Meng Wu at SIBCB for NMR data acquirement and analysis. This work was supported by grants from the National Natural Science Foundation of China (31270773 and 31470758), and the National Basic Research Program of China (2012CB911003).

Publisher Copyright:
© 2017 The Author(s).

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