Huntington's Disease (HD) is a monogenetic neurodegenerative disorder mainly caused by the cytotoxicity of the mutant HTT protein (mHTT) encoded by the mutant HTT gene. Lowering HTT mRNA has been extensively studied as a potential therapeutic strategy, but how its level is regulated endogenously has been unclear. Here we report that the RNA-binding protein (RBP) HuR interacts with and stabilizes HTT mRNA in an mHTT-dependent manner. In HD cells but not wild-type cells, siRNA knockdown or CRISPR-induced heterozygous knockout of HuR decreased HTT mRNA stability. HuR interacted with HTT mRNA at a conserved site in exon 11 rather than the 3'-UTR region of the mRNA. Interestingly, this interaction was dependent on the presence of mHTT, likely via the activation of MAPK11, which enhanced cytosolic localization of the HuR protein. Thus, mHTT, MAPK11 and HuR may form a positive feedback loop that stabilizes HTT mRNA and enhances mHTT accumulation, which may contribute to HD progression. Our data reveal a novel regulatory mechanism of HTT mRNA via non-canonical binding of HuR.

中文翻译：

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HuR通过以依赖于HTT的突变方式与其外显子11相互作用来稳定HTT mRNA。

亨廷顿舞蹈病（HD）是一种单基因性神经退行性疾病，主要由突变型HTT基因编码的突变型HTT蛋白（mHTT）的细胞毒性引起。降低HTT mRNA作为一种潜在的治疗策略已得到广泛研究，但尚不清楚如何内源调节其水平。在这里我们报告说，RNA结合蛋白（RBP）HuR与mHTT依赖的方式相互作用并稳定HTT mRNA。在HD细胞而非野生型细胞中，siRNA敲低或CRISPR诱导的HuR杂合敲除降低了HTT mRNA的稳定性。HuR在外显子11的保守位点而不是mRNA的3'-UTR区与HTT mRNA相互作用。有趣的是，这种相互作用可能依赖于mHTT的存在，可能是通过MAPK11的激活来实现的，该激活增强了HuR蛋白的胞质定位。因此，mHTT MAPK11和HuR可能形成一个稳定HTT mRNA并增强mHTT积累的正反馈回路，这可能有助于HD进程。我们的数据揭示了通过非规范的HuR结合的HTT mRNA的新型调节机制。