Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Aging (Upcoming)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor–mediated disease
Jason P. Chua, … , Jorge A. Iñiguez-Lluhí, Andrew P. Lieberman
Jason P. Chua, … , Jorge A. Iñiguez-Lluhí, Andrew P. Lieberman
Published January 20, 2015
Citation Information: J Clin Invest. 2015;125(2):831-845. https://doi.org/10.1172/JCI73214.
View: Text | PDF
Research Article

Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor–mediated disease

  • Text
  • PDF
Abstract

Expansion of the polyglutamine (polyQ) tract within the androgen receptor (AR) causes neuromuscular degeneration in individuals with spinobulbar muscular atrophy (SBMA). PolyQ AR has diminished transcriptional function and exhibits ligand-dependent proteotoxicity, features that have both been implicated in SBMA; however, the extent to which altered AR transcriptional function contributes to pathogenesis remains controversial. Here, we sought to dissociate effects of diminished AR function from polyQ-mediated proteotoxicity by enhancing the transcriptional activity of polyQ AR. To accomplish this, we bypassed the inhibitory effect of AR SUMOylation (where SUMO indicates small ubiquitin-like modifier) by mutating conserved lysines in the polyQ AR that are sites of SUMOylation. We determined that replacement of these residues by arginine enhances polyQ AR activity as a hormone-dependent transcriptional regulator. In a murine model, disruption of polyQ AR SUMOylation rescued exercise endurance and type I muscle fiber atrophy; it also prolonged survival. These changes occurred without overt alterations in polyQ AR expression or aggregation, revealing the favorable trophic support exerted by the ligand-activated receptor. Our findings demonstrate beneficial effects of enhancing the transcriptional function of the ligand-activated polyQ AR and indicate that the SUMOylation pathway may be a potential target for therapeutic intervention in SBMA.

Authors

Jason P. Chua, Satya L. Reddy, Zhigang Yu, Elisa Giorgetti, Heather L. Montie, Sarmistha Mukherjee, Jake Higgins, Richard C. McEachin, Diane M. Robins, Diane E. Merry, Jorge A. Iñiguez-Lluhí, Andrew P. Lieberman

×

Figure 1

A cellular model expressing non-SUMOylatable polyQ AR.

Options: View larger image (or click on image) Download as PowerPoint
A cellular model expressing non-SUMOylatable polyQ AR.
(A) AR10Q, AR112Q...
(A) AR10Q, AR112Q, or AR111Q-KRKR were induced to express AR in the presence of 10 nM R1881 for 24 hours, then analyzed by Western blot. Dox, doxycycline. (B and C) AR10Q, AR112Q, and AR111Q-KRKR cells were induced to express AR for 24 hours, then treated with R1881 for varying times and immunostained for AR (red). Nuclei were stained by DAPI. (B) Cytoplasmic (score 0) to nuclear (score 4) translocation was determined at indicated times. Data are mean ± SEM. n = 3 replicate experiments. (C) Arrows indicate nuclei containing aggregates after 24 hours of treatment with 10 nM R1881. Scale bar: 2 μm. (D) AR112Q- and AR111Q-KRKR–expressing cells were transfected with HA-SUMO3 and treated with 10 nM R1881 for 24 hours. Whole-cell lysates (left panel) were immunoprecipitated for AR and blotted for HA or AR (right panel). (E) AR112Q or AR111Q-KRKR cells were transfected with HA-ubiquitin and hCHIP, and treated with YM-1, as indicated. Following incubation with 10 mM MG132, lysates were collected and analyzed for AR ubiquitination. Whole-cell lysates (left panel) were immunoprecipitated for AR and blotted for AR and HA (middle and right panels).

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts