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

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.

Proteostasis in Huntington's disease: disease mechanisms and therapeutic opportunities

“…of HSP90, and direct binding of HSP90 to exon 1 at N17 was recently demonstrated [51] . This study also showed that USP19 may be subsequently recruited to HSP90-HTT fragment complexes and can then deubiquitylate HTT, leading to accumulation of insoluble HTT aggregates containing HSP90.…”

“…Surprisingly, few DUBs have been reported to deubiquitylate HTT. ATXN3, a DUB that itself contains a polyQ tract, and USP19 are the only known DUBs to target HTT [49][50][51] besides UPS. Monoubiquitylation or ubiquitin conjugation of proteins by different linkages of chains are recognised by a range of proteins containing ubiquitin binding domains (UBDs) or ubiquitininteracting motifs (UIMs) and are essential in numerous cell signalling pathways.…”

USP19 deubiquitinates EWS-FLI1 to regulate Ewing sarcoma growth

“…At the C-terminal end, USP19 harbors a transmembrane domain mapping its function initially to endoplasmic-reticulum-associated degradation and cellular homeostasis by supporting protein quality control and clearing misfolded proteins, mainly in interaction with the chaperone Hsp90 25–28 . USP19 seems to contribute different biological mechanisms such as protection against muscle wasting 29–31 , formation of protein aggregation 28,32 or cell proliferation 33,34 . There, USP19 depletion inhibited proliferation of prostate cancer and breast epithelial cell lines suggesting it to have oncogenic properties 33,34 .…”

Widespread remodelling of proteome solubility in response to different protein homeostasis stresses

“…Interestingly, the proteins upregulated suggested a role in stabilizing, rather than degrading Httex1. This included deubiquitinating enzyme Usp19, which has been previously reported to stabilize mutant Httex1 levels and promote its aggregation into less toxic aggregates by Hsp90 (102,103). Rock2 was also increased, which has previously been suggested to slow degradation of Httex1 (104).…”