Phosphorylation of Profilin by ROCK1 Regulates Polyglutamine Aggregation

作者：Jieya Shao, William J. Welch, Nicholas A. DiProspero, Marc I. Diamond · 发表于：Molecular and Cellular Biology · 年份：2008 · DOI：10.1128/mcb.00079-08 · 被引用次数：178 · 研究领域：Genetic Neurodegenerative Diseases、Muscle Physiology and Disorders、Mitochondrial Function and Pathology

Y-27632, an inhibitor of the Rho-associated kinase ROCK, is a therapeutic lead for Huntington disease (HD). The downstream targets that mediate its inhibitory effects on huntingtin (Htt) aggregation and toxicity are unknown. We have identified profilin, a small actin-binding factor that also interacts with Htt, as being a direct target of the ROCK1 isoform. The overexpression of profilin reduces the aggregation of polyglutamine-expanded Htt and androgen receptor (AR) peptides. This requires profilin's G-actin binding activity and its direct interaction with Htt, which are both inhibited by the ROCK1-mediated phosphorylation of profilin at Ser-137. Y-27632 blocks the phosphorylation of profilin in HEK293 cells and primary neurons, which maintains profilin in an active state. The knockdown of profilin blocks the inhibitory effect of Y-27632 on both AR and Htt aggregation. A signaling pathway from ROCK1 to profilin thus controls polyglutamine protein aggregation and is targeted by a promising therapeutic lead for HD.