HuR stabilizes HTT mRNA via interacting with its exon 11 in a mutant HTT-dependent manner

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 3ʹ-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.

亨廷顿病（Huntington’s Disease，简称HD）系由HTT基因突变所编码的毒性突变HTT蛋白（mHTT）导致的单基因神经退行性疾病。降低HTT mRNA水平已被广泛研究作为潜在的治疗策略，但其内源性调节机制尚不明确。本研究报告，RNA结合蛋白（RBP）HuR以mHTT依赖性方式与HTT mRNA相互作用并稳定之。在亨廷顿病细胞而非野生型细胞中，siRNA敲低或CRISPR诱导的杂合子敲除HuR降低了HTT mRNA的稳定性。HuR与HTT mRNA在11外显子的保守位点而非mRNA的3'非翻译区（3'UTR）区域相互作用。有趣的是，这种相互作用依赖于mHTT的存在，可能通过激活MAPK11实现，这增强了HuR蛋白的细胞质定位。因此，mHTT、MAPK11和HuR可能形成一个正向反馈环，稳定HTT mRNA并增强mHTT的积累，这可能导致亨廷顿病的进展。我们的数据揭示了通过非典型结合HuR的HTT mRNA的新型调节机制。