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

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

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

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Figure 3

Generation of AR113Q-KRKR knockin mice.

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Generation of AR113Q-KRKR knockin mice. (A) Schematic representation dep...
(A) Schematic representation depicting AR113Q-KRKR targeting vector. Sphl restriction sites, 5′ and 3′ probes for Southern blot analysis, glutamine tract, lysine-to-arginine mutations, and floxed neomycin resistance cassette are indicated. Diagram modified from ref. 55. (B) Southern blot analysis of ES cell DNA after Sphl digestion with the 5′ and 3′ probes indicated in A before (lanes 1 and 4) and after (lanes 2 and 5) homologous recombination. Lanes 3 and 6 contain control liver DNA from previously targeted AR113Q knockin line. L, ladder. (C) PCR primers were used to amplify sequences from a WT female (lane 1), F1 AR113Q-KRKR female (lane 2), and N1 AR113Q-KRKR male (lane 3) produced by the female in lane 2.