Phosphorylation of profilin by ROCK1 regulates polyglutamine aggregation
Phosphorylation of profilin by ROCK1 regulates polyglutamine aggregation
复制标题
DOI：
10.1128/mcb.00079-08
复制
发表时间：
2008-09-01
影响因子：
5.3
通讯作者：
Diamond, Marc I.
中科院分区：
文献类型：
--
作者：
Shao, Jieya;Welch, William J.;Diamond, Marc I.
Y-27632是Rho相关激酶ROCK的抑制剂，是治疗亨廷顿病（HD）的先导药物。介导其对亨廷顿蛋白（Htt）聚集和毒性的抑制作用的下游靶点尚不清楚。我们已经确定profilin，一个小肌动蛋白结合因子，也与Htt相互作用，作为ROCK 1亚型的直接目标。profilin的过表达减少了聚谷氨酰胺扩增的Htt和雄激素受体（AR）肽的聚集。这需要profilin的G-肌动蛋白结合活性及其与Htt的直接相互作用，这两者都被ROCK 1介导的profilin在Ser-137的磷酸化抑制。Y-27632阻断HEK 293细胞和原代神经元中profilin的磷酸化，从而维持profilin处于活性状态。profilin的敲低阻断了Y-27632对AR和Htt聚集的抑制作用。因此，从ROCK 1到profilin的信号传导途径控制多聚谷氨酰胺蛋白聚集，并被有希望的HD治疗先导物靶向。
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.