title: RNA-binding Protein Quaking StabilizesSirt2mRNA during Oligodendroglial Differentiation.
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. Inquaking 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 toSirt2mRNA 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 ofSirt2.1andSirt2.2transcripts leading to increased accumulation ofSirt2transcripts. Consistent with this, overexpression ofqkIpromoted the expression ofSirt2mRNA and protein. However, overexpression of the nuclear isoformqkI-5promoted the expression ofSirt2mRNA, 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 ofSirt2mRNA for translation. Collectively, our study demonstrates that QKI directly plays a crucial role in the post-transcriptional regulation and expression ofSirt2to facilitate OL differentiation.
authors.affiliation: From the Laboratory of Molecular Cell Biology, College of Pharmacy and Nutrition and.|the Neuroscience Research Cluster, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.
authors.forename: Merlin P
authors.initials: MP
authors.lastname: Thangaraj
authors.affiliation: From the Laboratory of Molecular Cell Biology, College of Pharmacy and Nutrition and.|the Neuroscience Research Cluster, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.
authors.forename: Kendra L
authors.initials: KL
authors.lastname: Furber
authors.affiliation: From the Laboratory of Molecular Cell Biology, College of Pharmacy and Nutrition and.|the Neuroscience Research Cluster, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.
authors.forename: Jotham K
authors.initials: JK
authors.lastname: Gan
authors.affiliation: From the Laboratory of Molecular Cell Biology, College of Pharmacy and Nutrition and.|the Neuroscience Research Cluster, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.|the Department of Biochemistry and Molecular Biology, Medical School, Henan University, Kaifeng 475004, China.
authors.forename: Shaoping
authors.initials: S
authors.lastname: Ji
authors.affiliation: From the Laboratory of Molecular Cell Biology, College of Pharmacy and Nutrition and.|the Neuroscience Research Cluster, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.
authors.forename: Larhonda
authors.initials: L
authors.lastname: Sobchishin
authors.affiliation: the Neuroscience Research Cluster, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.|Department of Anatomy and Cell Biology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.|the Cameco Multiple Sclerosis Neuroscience Research Center, City Hospital, Saskatoon, Saskatchewan S7K 0M7, Canada, and.
authors.forename: J Ronald
authors.initials: JR
authors.lastname: Doucette
authors.affiliation: From the Laboratory of Molecular Cell Biology, College of Pharmacy and Nutrition and aj.nazarali@usask.ca.|the Neuroscience Research Cluster, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.|the Cameco Multiple Sclerosis Neuroscience Research Center, City Hospital, Saskatoon, Saskatchewan S7K 0M7, Canada, and.
authors.forename: Adil J
authors.initials: AJ
authors.lastname: Nazarali
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D005786:Gene Expression Regulation; D051379:Mice; D009836:Oligodendroglia / Q000166:cytology*; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D020218:Response Elements; D056565:Sirtuin 2 / Q000235:genetics*
chemical_list: D020033:Protein Isoforms; C098217:Qk protein, mouse; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2
keywords: RNA binding protein; Sirtuin 2; differentiation; mRNA stability; myelin; oligodendrocyte; post-transcriptional regulation; quaking response element; sirtuin