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

Quan Zhao; Chen Li; Meng Yu; Yimin Sun; Jian Wang; Lixiang Ma; Xiaoli Sun; Boxun Lu

doi:10.1080/15476286.2020.1712894

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

RNA Biol. 2020 Apr;17(4):500-516. doi: 10.1080/15476286.2020.1712894. Epub 2020 Jan 13.

Authors

Quan Zhao¹, Chen Li¹, Meng Yu¹, Yimin Sun¹, Jian Wang¹, Lixiang Ma², Xiaoli Sun^{1

3}, Boxun Lu¹

Affiliations

¹ Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, School of Life Sciences, Fudan University, Shanghai, China.
² Department of Anatomy, Histology and Embryology, Shanghai Basic Medical College, Fudan University, Shanghai, China.
³ Shanghai Xuhui District Central Hospital, Zhongshan Xuhui Hospital, Fudan University, Shanghai, China.

Abstract

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.

Keywords: CAG repeats; Huntington’s disease; MAPK; RNA binding protein; neurodegeneration; p38; polyglutamine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions
Animals
Binding Sites
CRISPR-Cas Systems
Cell Line
ELAV-Like Protein 1 / genetics
ELAV-Like Protein 1 / metabolism*
Exons
Feedback, Physiological
Gene Knockdown Techniques
HEK293 Cells
Humans
Huntingtin Protein / chemistry*
Huntingtin Protein / genetics*
Huntington Disease / genetics*
Huntington Disease / metabolism
Mice
Mitogen-Activated Protein Kinase 11 / metabolism*
Mutation*
RNA Stability

Substances

3' Untranslated Regions
ELAV-Like Protein 1
ELAVL1 protein, human
HTT protein, human
Huntingtin Protein
Mitogen-Activated Protein Kinase 11

Grants and funding

Project Supported by National Natural Science Foundation of China [31970747, 31601105, 81870990, 81925012], Science and Technology Commission of Shanghai Municipality [18410722100], Shanghai Municipal Science and Technology Major Project [No.2018SHZDZX01] and ZJLab, and Hereditary Disease Foundation for funding supports. Funding for open access charge: National Natural Science Foundation of China.