The QKI-PLP pathway controls SIRT2 abundance in CNS myelin.
The QKI-PLP pathway controls SIRT2 abundance in CNS myelin.
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作者：
Zhu, H.;Zhao, L.;Wang, E.;Dimova, N.;Liu, G.;Feng, Y.;Cambi, F.
Sirtuin 2（SIRT 2）是一种NAD依赖性脱乙酰酶，由中枢神经系统（CNS）的髓鞘生成细胞--少突胶质细胞（OLs）表达，在活跃的髓鞘形成过程中显著上调。SIRT 2是髓鞘蛋白质组的一个组成部分，在PLP和DM 20都不存在的Plp 1敲除小鼠脑中严重减少。SIRT 2在OLs和髓磷脂中表达的调控机制仍有待研究。我们首次报道SIRT 2的表达受QKI依赖性通路的调节，这种作用是通过选择性调节PLP介导的。在OLs中存在QKI缺陷的纯合子quakingviable（qqs/qqs）突变小鼠中，PLP而不是DM 20 mRNA被选择性下调，SIRT 2蛋白严重减少，而SIRT 2 mRNA表达不受影响。在OL中表达细胞质同种型QKI 6拯救了qRT 3/qRT 4突变体中的SIRT 2表达，同时恢复了PLP表达。此外，SIRT 2蛋白在PLP-ISEdel突变体脑的髓鞘束和致密髓鞘中减少，其中PLP蛋白而不是DM 20被选择性地减少。相比之下，SIRT 2表达及其在调节过程复杂性中的细胞功能不受PLP-ISEdel非髓鞘化少突胶质细胞中PLP缺乏的影响。总的来说，我们的结果表明，髓鞘中SIRT 2的丰度依赖于PLP，而不是DM 20。
Sirtuin 2 (SIRT2), a NAD-dependent deacetylase expressed by oligodendrocytes (OLs), the myelin-producing cells of the central nervous system (CNS), is markedly up-regulated during active myelination. SIRT2 is a component of the myelin proteome and is severely reduced in the Plp1 knockout mouse brain, in which both PLP and DM20 are absent. The mechanisms that regulate SIRT2 expression in OLs and myelin remain to be investigated. We report for the first time that the expression of SIRT2 is regulated by the QKI-dependent pathway and this effect is mediated through selective regulation of PLP. In the homozygous quakingviable (qkv/qkv) mutant mouse that harbors QKI deficiency in OLs, PLP, but not DM20 mRNA, was selectively down-regulated and SIRT2 protein was severely reduced while SIRT2 mRNA expression was unaffected. Expression of the cytoplasmic isoform QKI6 in OLs rescued SIRT2 expression in the qkv/qkv mutant concomitantly with restoration of PLP expression. Moreover, SIRT2 protein is diminished in myelin tracts and compact myelin of the PLP-ISEdel mutant brain, in which PLP protein but not DM20 is selectively reduced. In contrast, SIRT2 expression and its cellular function in regulating process complexity are not affected by the absence of PLP in PLP-ISEdel non-myelinating oligodendrocytes. Collectively, our results indicate that the abundance of SIRT2 in myelin is dependent on PLP, but not DM20.
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影响因子：
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