RNA-binding Protein Quaking Stabilizes Sirt2 mRNA during Oligodendroglial Differentiation

Merlin P Thangaraj,Kendra L Furber,Jotham K Gan,Shaoping Ji,Larhonda Sobchishin,J Ronald Doucette,Adil J Nazarali

doi:10.1074/jbc.m117.775544

Merlin P Thangaraj, Kendra L Furber + Show 5 more

Open Access

https://doi.org/10.1074/jbc.m117.775544

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Abstract

Myelination is controlled by timely expression of genes involved in the differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes (OLs). Sirtuin 2 (SIRT2), a NAD+-dependent deacetylase, plays a critical role in OL differentiation by promoting both arborization and downstream expression of myelin-specific genes. However, the mechanisms involved in regulating SIRT2 expression during OL development are largely unknown. The RNA-binding protein quaking (QKI) plays an important role in myelination by post-transcriptionally regulating the expression of several myelin specific genes. In quaking viable (qkv/qkv ) mutant mice, SIRT2 protein is severely reduced; however, it is not known whether these genes interact to regulate OL differentiation. Here, we report for the first time that QKI directly binds to Sirt2 mRNA via a common quaking response element (QRE) located in the 3' untranslated region (UTR) to control SIRT2 expression in OL lineage cells. This interaction is associated with increased stability and longer half-lives of Sirt2.1 and Sirt2.2 transcripts leading to increased accumulation of Sirt2 transcripts. Consistent with this, overexpression of qkI promoted the expression of Sirt2 mRNA and protein. However, overexpression of the nuclear isoform qkI-5 promoted the expression of Sirt2 mRNA, but not SIRT2 protein, and delayed OL differentiation. These results suggest that the balance in the subcellular distribution and temporal expression of QKI isoforms control the availability of Sirt2 mRNA for translation. Collectively, our study demonstrates that QKI directly plays a crucial role in the post-transcriptional regulation and expression of Sirt2 to facilitate OL differentiation.

Highlights

Myelination is controlled by timely expression of genes involved in the differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes (OLs)
In OLs, efficient binding of QKI to quaking response element (QRE) has been reported for transcripts of myelin basic protein (MBP) [6, 7, 18, 19], myelin-associated glycoprotein (Mag) [8], cyclin-dependent kinase inhibitor p27Kip1 [20], actin interacting protein 1 (Aip-1) [21], microtubule-associated protein 1B (Map1B) [22], and heterologous nuclear ribonucleoprotein A1 [23]
Expression of QKI and Sirtuin 2 (SIRT2) Increase during OL Differentiation—QKI plays a critical role in OL differentiation by regulating the expression of several myelin specific genes, such as Mbp [6, 7], Plp [9], and Mag [8, 10, 42]

Summary

Introduction

Myelination is controlled by timely expression of genes involved in the differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes (OLs). In OLs, efficient binding of QKI to QREs has been reported for transcripts of myelin basic protein (MBP) [6, 7, 18, 19], myelin-associated glycoprotein (Mag) [8], cyclin-dependent kinase inhibitor p27Kip1 [20], actin interacting protein 1 (Aip-1) [21], microtubule-associated protein 1B (Map1B) [22], and heterologous nuclear ribonucleoprotein A1 (hnRNPA1) [23] This interaction alters the stability of the target mRNAs, which can lead to either a promotion or inhibition in the downstream translation of the protein products, as is the case for p27Kip1 [20] or Aip-1 [21], respectively. It was postulated that QKI indirectly regulates SIRT2 expression during CNS myelination through co-transport with PLP into the myelin sheath [25]

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