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

Authors

Jason P Chua, Department of Pathology, University of Michigan, Medical School; Neuroscience Graduate Program, University of Michigan; Medical Scientist Training Program, University of Michigan
Satya L Reddy, Department of Pathology, University of Michigan, Medical School
Zhigang Yu, Department of Pathology, University of Michigan, Medical School
Elisa Giorgetti, Department of Pathology, University of Michigan, Medical School
Heather L Montie, Department of Biochemistry and Molecular Biology, Thomas Jefferson University; Department of Bio-Medical Sciences, Philadelphia College of Osteopathic MedicineFollow
Sarmistha Mukherjee, Department of Pharmacology, University of Michigan
Jake Higgins, Department of Human Genetics, University of Michigan
Richard C McEachin, Department of Computational Medicine and Bioinformatics, University of Michigan
Diane M Robins, Department of Human Genetics, University of Michigan
Diane E Merry, Department of Biochemistry and Molecular Biology, Thomas Jefferson UniversityFollow
Jorge A Iñiguez-Lluhí, Department of Pharmacology, University of Michigan
Andrew P Lieberman, Department of Pathology, University of Michigan, Medical School

Document Type

Article

Publication Date

2-2-2015

Comments

This article has been peer reviewed. It was published in: Journal of Clinical Investigation.

Volume 125, Issue 2, 2 February 2015, Pages 831-845.

The published version is available at DOI: 10.1172/JCI73214

Copyright © 2015, American Society for Clinical Investigation

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.

Recommended Citation

Chua, Jason P; Reddy, Satya L; Yu, Zhigang; Giorgetti, Elisa; Montie, Heather L; Mukherjee, Sarmistha; Higgins, Jake; McEachin, Richard C; Robins, Diane M; Merry, Diane E; Iñiguez-Lluhí, Jorge A; and Lieberman, Andrew P, "Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor-mediated disease." (2015). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 96.
https://jdc.jefferson.edu/bmpfp/96

PubMed ID

25607844