Cytoplasmic Ubiquitin-Specific Protease 19 (USP19) Modulates Aggregation of Polyglutamine-Expanded Ataxin-3 and Huntingtin through the HSP90 Chaperone

PloS One
Wen-Tian HeHong-Yu Hu

Abstract

Ubiquitin-specific protease 19 (USP19) is one of the deubiquitinating enzymes (DUBs) involved in regulating the ubiquitination status of substrate proteins. There are two major isoforms of USP19 with distinct C-termini; the USP19_a isoform has a transmembrane domain for anchoring to the endoplasmic reticulum, while USP19_b contains an EEVD motif. Here, we report that the cytoplasmic isoform USP19_b up-regulates the protein levels of the polyglutamine (polyQ)-containing proteins, ataxin-3 (Atx3) and huntingtin (Htt), and thus promotes aggregation of their polyQ-expanded species in cell models. Our data demonstrate that USP19_b may orchestrate the stability, aggregation and degradation of the polyQ-expanded proteins through the heat shock protein 90 (HSP90) chaperone system. USP19_b directly interacts with HSP90 through its N-terminal CS (CHORD and SGT1)/P23 domains. In conjunction with HSP90, the cytoplasmic USP19 may play a key role in triage decision for the disease-related polyQ-expanded substrates, suggesting a function of USP19 in quality control of misfolded proteins by regulating their protein levels.

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Citations

Mar 17, 2018·Journal of Glaucoma·Audrey M BernsteinJose M Wolosin
Oct 12, 2019·International Journal of Molecular Sciences·Anastasiia BohushAnna Filipek
Mar 23, 2017·Genome Medicine·Mohammad K EldomeryJames R Lupski
Sep 7, 2018·Molecular Neurobiology·Naila S AshrafMaria do Carmo Costa
Jul 19, 2020·International Journal of Molecular Sciences·Neha SarodayaSuresh Ramakrishna
Apr 7, 2017·Frontiers in Molecular Neuroscience·Samir R Nath, Andrew P Lieberman
Feb 1, 2019·Scientific Reports·Maria E GierischBeat W Schäfer
Nov 20, 2020·Cell Death and Differentiation·François Le Guerroué, Richard J Youle

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Methods Mentioned

BETA
ubiquitination
deubiquitination
PCR
transfections
transfection
co-IP
filter trap
pull-down
filter
immunoprecipitation

Software Mentioned

Scion Image

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