HuR Stabilizes HTT mRNA via Interacting with Its Exon 11 in a Mutant HTT-Dependent Manner
HuR Stabilizes HTT mRNA via Interacting with Its Exon 11 in a Mutant HTT-Dependent Manner
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HuR 通过以突变 HTT 依赖性方式与其外显子 11 相互作用来稳定 HTT mRNA。
DOI：
10.1080/15476286.2020.1712894
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发表时间：
2020-01
期刊：
影响因子：
4.1
通讯作者：
Boxun Lu
中科院分区：
文献类型：
--
作者：
Quan Zhao;Chen Li;Meng Yu;Yimin Sun;Jian Wang;Lixiang Ma;Xiaoli Sun;Boxun Lu
亨廷顿病（HD）是一种单基因遗传性神经退行性疾病，主要由突变HTT基因编码的突变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被广泛研究，但其水平如何内源性调节尚不清楚。在这里，我们报告的RNA结合蛋白（RBP）HuR相互作用，并稳定HTT mRNA的mHTT依赖的方式。在HD细胞而不是野生型细胞中，siRNA敲低或CRISPR诱导的HuR杂合敲除降低了HTT mRNA的稳定性。HuR与HTT mRNA相互作用的保守位点在外显子11而不是mRNA的3 '-UTR区域。有趣的是，这种相互作用依赖于mHTT的存在，可能是通过激活MAPK 11，这增强了HuR蛋白的胞质定位。因此，mHTT、MAPK 11和HuR可能形成一个正反馈环，稳定HTT mRNA并增强mHTT蓄积，这可能有助于HD进展。我们的数据揭示了HTT mRNA通过HuR的非经典结合的新的调节机制。
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.
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