Phosphorylation of profilin by ROCK1 regulates polyglutamine aggregation.
Article Details
- CitationCopy to clipboard
Shao J, Welch WJ, Diprospero NA, Diamond MI
Phosphorylation of profilin by ROCK1 regulates polyglutamine aggregation.
Mol Cell Biol. 2008 Sep;28(17):5196-208. doi: 10.1128/MCB.00079-08. Epub 2008 Jun 23.
- PubMed ID
- 18573880 [ View in PubMed]
- Abstract
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.