Phosphorylation of profilin by ROCK1 regulates polyglutamine aggregation

Jieya Shao, William J. Welch, Nicholas A. DiProspero, Marc I. Diamond

Research output: Contribution to journalArticle

95 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5196-5208
Number of pages13
JournalMolecular and cellular biology
Volume28
Issue number17
DOIs
StatePublished - Sep 1 2008

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Phosphorylation of profilin by ROCK1 regulates polyglutamine aggregation'. Together they form a unique fingerprint.

  • Cite this