RNA-binding Protein Quaking Stabilizes Sirt2 mRNA 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. In ) 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 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 and transcripts leading to increased accumulation of transcripts. Consistent with this, overexpression of promoted the expression of mRNA and protein. However, overexpression of the nuclear isoform promoted the expression of 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 mRNA for translation. Collectively, our study demonstrates that QKI directly plays a crucial role in the post-transcriptional regulation and expression of to facilitate OL differentiation.

Down‐regulation of interleukin‐33 expression in oligodendrocyte precursor cells impairs oligodendrocyte lineage progression

“…Indeed, the in vitro data from the examination of OLG differentiation from the IL33‐KD OPCs or IL33‐KO OPCs provide evidence that the differentiation of OLGs was impaired along with declined expression of the critical OLG transcript factor, Olig2. Sirt2, which is localized in the paranodal regions of the CNS myelin sheath, is expressed at an early stage of OLG differentiation (Li et al ; Ji et al ; Thangaraj et al ). Thus, reduced expression of Sirt2 in OPCs by IL33‐KD could be a factor causing inhibition in OLG differentiation, or it could be a consequence from the suppression of OLG differentiation.…”

Sirtuin 2 enhances allergic asthmatic inflammation

“…Although a predicted Sirt2 isoform 4 variant is in the GenBank database, the predicted protein structure and functionality of this isoform have yet to be determined. Several groups have identified a third variant of Sirt2, which has been referred to as isoform 3, found in mice and rats (23,25), as well as isoform 5, found in humans (24). Because we examine expression of the Sirt2 isoforms using both human and murine samples, we have chosen to refer to the third isoform as Sirt2 isoform 3/5.…”

“…There are several different isoforms of Sirt2 found in both human and mouse samples. Previous work has determined that these isoforms result from alternative splicing mechanisms rather than protein degradation (23)(24)(25). Sirt2 isoforms 1 and 2 are most similar and are localized in the cytoplasm under resting conditions (23,24).…”

Hoxa2 Inhibits Bone Morphogenetic Protein Signaling during Osteogenic Differentiation of the Palatal Mesenchyme

“…First strand complementary DNA synthesis (reverse transcription) was performed in 20 μl reactions with 500 ng of total RNA using High-Capacity complementary DNA Reverse Transcription Kit (Invitrogen). qRT-PCR was carried out as described in our previous study (Thangaraj et al, 2017 ) using SYBR green assay (Applied Biosystems) in 7300-real time PCR system (Applied Biosystems) with primers listed in Table 1 .…”