The College of Life Sciences, Zhejiang University, Hangzhou, 310058, China.
Institute of Life Sciences, Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, 310018, China, and.
J Neurosci. 2018 Nov 14;38(46):9829-9839. doi: 10.1523/JNEUROSCI.0154-18.2018. Epub 2018 Sep 24.
Myelin sheath formed by oligodendrocytes (OLs) is essential for the rapid propagation of action potentials in the vertebrate CNS. Myelin regulatory factor (MYRF) is one of the critical factors that control OL differentiation and myelin maintenance. Previous studies showed that MYRF is a membrane-bound transcription factor associated with the endoplasmic reticulum (ER). After self-cleavage, the N-fragment of MYRF is released from the ER and translocated into the nucleus where it functions as a transcription factor to activate myelin gene expression. At present, it remains unknown whether MYRF self-cleavage and functional activation can be regulated during OL differentiation. Here, we report that TMEM98, an ER-associated transmembrane protein, is capable of binding to the C-terminal of MYRF and inhibiting its self-cleavage and N-fragment nuclear translocation. In the developing CNS, TMEM98 is selectively expressed in early maturing OLs in mouse pups of either sex. Forced expression of TMEM98 in embryonic chicken spinal cord of either sex suppresses endogenous OL differentiation and MYRF-induced ectopic expression of myelin genes. These results suggest that TMEM98, through inhibiting the self-cleavage of MYRF, functions as a negative feedback regulator of MYRF in oligodendrocyte differentiation and myelination. MYRF protein is initially synthesized as an ER-associated membrane protein that undergoes autoproteolytic cleavage to release the N-fragment, which is then transported into the nucleus and activates the transcription of myelin genes. To date, the molecular mechanisms that regulate the self-cleavage and function of MYRF in regulating oligodendrocyte differentiation have remained unknown. In this study, we present the molecular and functional evidence that TMEM98 membrane protein physically interacts with MYRF in the ER and subsequently blocks its self-cleavage, N-terminal nuclear translocation, and functional activation of myelin gene expression. To our knowledge, this is the first report on the regulation of MYRF self-proteolytic activity and function by an interacting protein, providing new insights into the molecular regulation of OL differentiation and myelinogenesis.
少突胶质细胞（OLs）形成的髓鞘对于脊椎动物中枢神经系统中动作电位的快速传播至关重要。髓鞘调节因子（MYRF）是控制 OL 分化和髓鞘维持的关键因素之一。先前的研究表明，MYRF 是一种与内质网（ER）相关的膜结合转录因子。自我切割后，MYRF 的 N 片段从 ER 中释放出来，并转移到细胞核中，在细胞核中作为转录因子激活髓鞘基因表达。目前，尚不清楚在 OL 分化过程中 MYRF 的自我切割和功能激活是否可以受到调节。在这里，我们报告 ER 相关跨膜蛋白 TMEM98 能够与 MYRF 的 C 末端结合并抑制其自我切割和 N 片段核易位。在发育中的中枢神经系统中，TMEM98 在雄性和雌性幼鼠的早期成熟 OL 中选择性表达。在雄性和雌性胚胎鸡脊髓中强制表达 TMEM98 会抑制内源性 OL 分化和 MYRF 诱导的髓鞘基因异位表达。这些结果表明，TMEM98 通过抑制 MYRF 的自我切割，作为 MYRF 在少突胶质细胞分化和髓鞘形成中的负反馈调节剂发挥作用。MYRF 蛋白最初作为一种与内质网相关的膜蛋白合成，通过自蛋白水解切割释放 N 片段，然后该片段被转运到细胞核中并激活髓鞘基因的转录。迄今为止，调节 MYRF 在调节少突胶质细胞分化中的自我切割和功能的分子机制仍不清楚。在这项研究中，我们提供了分子和功能证据，证明 TMEM98 膜蛋白在 ER 中与 MYRF 物理相互作用，随后阻止其自我切割、N 端核易位和髓鞘基因表达的功能激活。据我们所知，这是关于相互作用蛋白调节 MYRF 自我切割活性和功能的首次报道，为 OL 分化和髓鞘发生的分子调控提供了新的见解。
