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Molecular and Cellular Biology, September 2008, p. 5196-5208, Vol. 28, No. 17
0270-7306/08/$08.00+0     doi:10.1128/MCB.00079-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Phosphorylation of Profilin by ROCK1 Regulates Polyglutamine Aggregation {triangledown}

Jieya Shao,1 William J. Welch,2 Nicholas A. DiProspero,3 and Marc I. Diamond1*

Departments of Neurology and Cellular and Molecular Pharmacology, UCSF, San Francisco, California 94143,1 Department of Surgery, UCSF, San Francisco, California 94143,2 Neurogenetics Branch, NIH, Bethesda, Maryland 208923

Received 15 January 2008/ Returned for modification 4 February 2008/ Accepted 12 June 2008

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.

* Corresponding author. Mailing address: GH-S572B, UCSF, 600 16th Street, San Francisco, CA 94143-2280. Phone: (415) 514-3646. Fax: (415) 514-4112. E-mail: marc.diamond{at}ucsf.edu

{triangledown} Published ahead of print on 23 June 2008.

Molecular and Cellular Biology, September 2008, p. 5196-5208, Vol. 28, No. 17
0270-7306/08/$08.00+0     doi:10.1128/MCB.00079-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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