Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas, 46010 Valencia, Spain.
Proc Natl Acad Sci U S A. 2013 Sep 3;110(36):14729-34. doi: 10.1073/pnas.1216844110. Epub 2013 Aug 19.
Mutations in PTEN-induced putative kinase 1 (PINK1) gene are associated to early-onset recessive forms of Parkinson disease. PINK1 function is related to mitochondria homeostasis, but the molecular pathways in which PINK1 is involved are largely unknown. Here, we report the identification of the embryonic ectoderm development polycomb histone-methylation modulator (EED/WAIT1) as a PINK1-interacting and -regulated protein. The PINK1:EED/WAIT1 physical interaction was mediated by the PINK1 kinase domain and the EED/WAIT1 40 amino acid ending with tryptophan and aspartate (WD40)-repeat region, and PINK1 phosphorylated EED/WAIT1 in vitro. PINK1 associated with EED/WAIT1 in cells and relocated EED/WAIT1 to the mitochondria. This interaction reduced the trimethylation of lysine 27 from histone H3, which affected polycomb-regulated gene transcription during RA differentiation of SH-SY5Y human neuroblastoma cells. Our findings unveil a pathway by which PINK1 regulates histone methylation and gene expression through the polycomb repressor complex.
PTEN 诱导的假定激酶 1（PINK1）基因突变与早发性常染色体隐性形式的帕金森病有关。PINK1 的功能与线粒体稳态有关，但 PINK1 参与的分子途径在很大程度上尚不清楚。在这里，我们报告鉴定胚胎外胚层发育多梳组蛋白甲基化调节剂（EED/WAIT1）作为 PINK1 相互作用和调节的蛋白。PINK1：EED/WAIT1 物理相互作用由 PINK1 激酶结构域和 EED/WAIT1 末端带有色氨酸和天冬氨酸（WD40）重复序列的 40 个氨基酸介导，并且 PINK1 在体外磷酸化 EED/WAIT1。PINK1 在细胞中与 EED/WAIT1 相关，并将 EED/WAIT1 重新定位到线粒体。这种相互作用减少了组蛋白 H3 赖氨酸 27 的三甲基化，这在 RA 分化的 SH-SY5Y 人神经母细胞瘤细胞中影响多梳调节的基因转录。我们的发现揭示了 PINK1 通过多梳抑制复合物调节组蛋白甲基化和基因表达的途径。
