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

Publication date: Jan 13, 2020

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.

Open Access PDF

Zhao, Q., Li, C., Yu, M., Sun, Y., Wang, J., Ma, L., Sun, X., and Lu, B. HuR stabilizes HTT mRNA via interacting with its exon 11 in a mutant HTT-dependent manner. 06876. 2020 RNA Biol.

Concepts Keywords
CRISPR Exon
Cytosolic Poly(A)-binding protein
Cytotoxicity Huntingtin
Exon Small interfering RNA
Gene Messenger RNA
Heterozygous Molecular genetics
Huntington Gene expression
Knockout RNA
Monogenetic Spliceosome
MRNA Nucleic acids
Mutant SiRNA
Neurodegenerative Disorder
Positive Feedback Loop
Protein
RNA
SiRNA
Wild Type

Semantics

Type Source Name
disease MESH neurodegenerative disorder

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