The hypoparathyroidism-associated mutation in Drosophila Gcm compromises protein stability and glial cell formation.
The hypoparathyroidism-associated mutation in Drosophila Gcm compromises protein stability and glial cell formation.
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果蝇 Gcm 中与甲状旁腺功能减退相关的突变损害蛋白质稳定性和神经胶质细胞形成
DOI：
10.1038/srep39856
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发表时间：
2017-01-04
影响因子：
4.6
通讯作者：
Ho MS
中科院分区：
文献类型：
--
作者：
Xi X;Lu L;Zhuge CC;Chen X;Zhai Y;Cheng J;Mao H;Yang CC;Tan BC;Lee YN;Chien CT;Ho MS
分化的神经元和胶质细胞是通过胶质细胞缺失家族(GCM)中的蛋白质等转录调控因子从未成熟的前体细胞获得的。哺乳动物的GCM蛋白介导神经干细胞的诱导、胎盘和甲状旁腺的发育，而果蝇的GCM蛋白则是决定神经元和神经胶质细胞命运和调节血细胞发育的关键开关。本研究报告了一个与甲状旁腺功能低下相关的突变R59L，该突变改变了果蝇GCM(GCM)蛋白的稳定性，使其不稳定，并通过泛素-蛋白酶体系统(UPS)实现了泛素化。GcmR59L与基于肢体的SCF复合体和蛋白激酶C(PKC)相互作用，可能在其磷酸化过程中发挥作用，从而改变泛素化。此外，R59L以一种独立于PEST结构域信号蛋白周转的方式导致GCM蛋白水平降低。GcmR59L蛋白结合DNA，功能激活转录，诱导胶质细胞，但效率较低。最后，无论是野生型人GCMB(HGcmb)还是携带保守的甲状旁腺功能低下突变的hGcmb的过表达只会对胶质形成产生轻微的影响，这表明人和苍蝇的调控机制不同。综上所述，这些发现证明了这种疾病相关突变在通过UPS控制GCM蛋白稳定性方面的重要性，从而促进了我们对胶质形成如何调控的理解。
Differentiated neurons and glia are acquired from immature precursors via transcriptional controls exerted by factors such as proteins in the family of Glial Cells Missing (Gcm). Mammalian Gcm proteins mediate neural stem cell induction, placenta and parathyroid development, whereas Drosophila Gcm proteins act as a key switch to determine neuronal and glial cell fates and regulate hemocyte development. The present study reports a hypoparathyroidism-associated mutation R59L that alters Drosophila Gcm (Gcm) protein stability, rendering it unstable, and hyperubiquitinated via the ubiquitin-proteasome system (UPS). GcmR59L interacts with the Slimb-based SCF complex and Protein Kinase C (PKC), which possibly plays a role in its phosphorylation, hence altering ubiquitination. Additionally, R59L causes reduced Gcm protein levels in a manner independent of the PEST domain signaling protein turnover. GcmR59L proteins bind DNA, functionally activate transcription, and induce glial cells, yet at a less efficient level. Finally, overexpression of either wild-type human Gcmb (hGcmb) or hGcmb carrying the conserved hypoparathyroidism mutation only slightly affects gliogenesis, indicating differential regulatory mechanisms in human and flies. Taken together, these findings demonstrate the significance of this disease-associated mutation in controlling Gcm protein stability via UPS, hence advance our understanding on how glial formation is regulated.
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