Phosphorylation of profilin by ROCK1 regulates polyglutamine aggregation.
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.
Shao
Jieya
J
Departments of Neurology and Cellular and Molecular Pharmacology, UCSF, San Francisco, California 94143, USA.
Welch
William J
WJ
Diprospero
Nicholas A
NA
Diamond
Marc I
MI
D000199:Actins / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002645:Chickens; D006801:Humans; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D051304:Profilins / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D020836:Protein Structure, Quaternary; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism*
D000199:Actins; D000577:Amides; D009419:Nerve Tissue Proteins; D010455:Peptides; D051304:Profilins; D011725:Pyridines; D011944:Receptors, Androgen; C108830:Y 27632; D010768:Phosphoserine; C097188:polyglutamine; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins