Inherited disorders of cobalamin metabolism disrupt nucleocytoplasmic transport of mRNA through impaired methylation/phosphorylation of ELAVL1/HuR

Nucleic Acids Research
Shyue-Fang Battaglia-HsuJean-Louis Guéant

Abstract

The molecular mechanisms that underlie the neurological manifestations of patients with inherited diseases of vitamin B12 (cobalamin) metabolism remain to date obscure. We observed transcriptomic changes of genes involved in RNA metabolism and endoplasmic reticulum stress in a neuronal cell model with impaired cobalamin metabolism. These changes were related to the subcellular mislocalization of several RNA binding proteins, including the ELAVL1/HuR protein implicated in neuronal stress, in this cell model and in patient fibroblasts with inborn errors of cobalamin metabolism and Cd320 knockout mice. The decreased interaction of ELAVL1/HuR with the CRM1/exportin protein of the nuclear pore complex and its subsequent mislocalization resulted from hypomethylation at R-217 produced by decreased S-adenosylmethionine and protein methyl transferase CARM1 and dephosphorylation at S221 by increased protein phosphatase PP2A. The mislocalization of ELAVL1/HuR triggered the decreased expression of SIRT1 deacetylase and genes involved in brain development, neuroplasticity, myelin formation, and brain aging. The mislocalization was reversible upon treatment with siPpp2ca, cobalamin, S-adenosylmethionine, or PP2A inhibitor okadaic acid. In co...Continue Reading

Citations

May 6, 2019·Cellular and Molecular Life Sciences : CMLS·Yueshuang KeXueqing Ba
Mar 22, 2020·Molecular Genetics & Genomic Medicine·Chao WangJianbo Shu
Jul 3, 2020·Nutrients·Joseph BoachiePonnusamy Saravanan
Aug 14, 2020·Cellular and Molecular Life Sciences : CMLS·Yueshuang KeXueqing Ba
Mar 19, 2020·Human Molecular Genetics·Jennifer L SloanCharles P Venditti
Jul 4, 2019·Biochimie·V Sudhakar ReddyG Bhanuprakash Reddy
Dec 31, 2020·Clinical and Translational Medicine·Mengqing XiaoKe Cao
Jan 17, 2020·Toxicology Letters·Xiaorong YangCe Zhang
Jul 23, 2021·Molecular Nutrition & Food Research·Pauline MoscaNatacha Dreumont
Oct 6, 2021·Critical Reviews in Biochemistry and Molecular Biology·Jean-Louis GuéantDavid Coelho

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Methods Mentioned

BETA
acetylation
transfection
Protein Assay
proximity ligation assay
electrophoresis
immunoprecipitation
PCR
RIP
co-IP
Duolink

Software Mentioned

Stata

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