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

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 conclusion, our data highlight the key role of the disruption of ELAVL1/HuR nuclear export, with genomic changes consistent with the effects of inborn errors of Cbl metabolisms on brain development, neuroplasticity and myelin formation.

Analysis of eEF1Bγ interactome in the nuclear fraction of A549 human lung adenocarcinoma cells

“…This protein is linked to Parkinson's disease [72]. Disruption of ELAVL1/HuR nuclear export is consistent with the effects of inborn errors of vitamin B12 (cobalamin) metabolisms on brain development, neuroplasticity and myelin formation [73].…”

HuRdling Senescence: HuR Breaks BRAF-Induced Senescence in Melanocytes and Supports Melanoma Growth

“…Research on other diseases suggests that the localization of HuR is of major importance for the function of this RBP. In studies on cobalamin metabolism disorders, the nucleocytoplasmic transport of HuR was shown to be disrupted as a result of dephosphorylation and hypomethylation of HuR, leading to decreased expression of genes involved in the cellular stress response, cell cycle regulation, neurogenesis, and neuroplasticity [35]. In a zebrafish model, changed phosphorylation of HuR led to the disruption of translocation and thereby to less stable gata1 mRNA and impaired formation of red blood cells [36].…”

Sirt1-PPARS Cross-Talk in Complex Metabolic Diseases and Inherited Disorders of the One Carbon Metabolism

“…The protective role of Sirt1 against oxidative stress is linked to the deacetylation of check point kinase 2, which increases cell death under oxidative stress [ 79 ]. We and others have shown a link between Sirt1 and RNA binding proteins like HUR in response to cellular stress [ 80 , 81 ]. Mitochondrion is one of the main organelle involved in ROS production [ 82 ].…”

“…The decreased expression of Sirt1 plays a prominent role in the pathomechanisms of fetal programming produced by MDD in rats (vitamin B12 and folate) [ 19 , 81 , 93 , 94 ]. Vitamin B12 is metabolized into two active cofactors, methyl-cobalamin (Me-Cbl) and adenosyl-cobalamin (Ado-Cbl), the cofactors for cytoplasmic methionine synthase (MS/MTR) and mitochondrial methyl malonyl CoA mutase, respectively [ 95 ].…”

“…The decreased interaction of ELAVL1/HuR with the CRM1/exportin protein of the nuclear pore complex and its subsequent mislocalization result from hypomethylation by decreased SAM and protein methyl transferase CARM1 and dephosphorylation by increased protein phosphatase PP2A. The mislocalization of ELAVL1/HuR triggers the decreased expression of Sirt1 deacetylase and other genes involved in brain development, neuroplasticity, myelin formation and brain aging [ 81 , 100 ]. In summary, Sirt1 plays a prominent role in the pathomechanisms produced by MDD through its role on the acetylation of PGC1α, the transcription of HSP and the subcellular localization of RNA binding proteins (RBP).…”