HspB1 silences translation of PDZ-RhoGEF by enhancing miR-20a and miR-128 expression to promote neurite extension.
HspB1 silences translation of PDZ-RhoGEF by enhancing miR-20a and miR-128 expression to promote neurite extension.
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DOI：
10.1016/j.mcn.2013.10.006
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发表时间：
2013-11
期刊：
影响因子：
--
通讯作者：
Mata M
中科院分区：
文献类型：
--
作者：
Sun X;Zhou Z;Fink DJ;Mata M
HspB 1是一种小的热休克蛋白，参与神经元的存活和神经突的生长; HspB 1的突变已在遗传性运动神经元病和Charcot玛丽牙2型神经病中被鉴定。在皮层神经元中，我们发现HspB 1的表达降低了RhoA活性和RhoA-GTP蛋白，并逆转了NogoA诱导的轴突延伸抑制。HspB 1减少PDZ-RhoGEF，RhoA特异性鸟嘌呤核苷酸交换因子，而RhoA活性的其他调节剂不变。PDZ-RhoGEF的减少不依赖于蛋白酶体或溶酶体降解途径，并且与PDZ-RhoGEF mRNA的变化无关。我们对大鼠PDZ-RhoGEF的3 'UTR进行了测序，发现了miRNAs miR-20 a、miR-128和miR-132的结合位点。这些microRNA的表达在转染HspB 1的皮质神经元中显著增加。HspB 1与miR-20 a或miR-128的特异性抑制剂共转染防止了PDZ-RhoGEF的减少并阻断了HspB 1的神经突生长促进作用。在荧光素酶报告基因构建体中使用PDZ-RhoGEF mRNA的3 'UTR，我们观察到HspB 1、miR-20 a和miR-128各自抑制荧光素酶表达。我们的结论是，HspB 1通过调节PDZ-RhoGEF水平来调节RhoA活性，PDZ-RhoGEF水平是通过增强特定miRNA（miR-20 a和miR-128）的表达来实现的翻译控制。通过PDZ-RhoGEF的翻译沉默调节RhoA活性可能是HspB 1参与神经突生长调节的机制。由于RhoA-GTdR通过其下游效应子在细胞骨架网络的组织和稳定性中起调节作用，因此结果表明HspB 1突变和轴突细胞骨架病理学之间可能存在联系。
HspB1 is a small heat shock protein implicated in neuronal survival and neurite growth; mutations in HspB1 have been identified in hereditary motor neuronopathies and Charcot Marie Tooth Type 2 neuropathies. In cortical neurons we found that expression of HspB1 decreased RhoA activity and RhoA-GTP protein, and reversed the inhibition of neurite extension induced by NogoA. HspB1 decreased PDZ-RhoGEF, a RhoA specific guanine nucleotide exchange factor, while other regulators of RhoA activity were unchanged. The decrease in PDZ-RhoGEF was independent of proteasomal or lysosomal degradation pathways and was not associated with changes in PDZ-RhoGEF mRNA. We sequenced the 3’UTR of rat PDZ-RhoGEF and found binding sites for miRNAs miR-20a, miR-128 and miR-132. Expression of these microRNAs was substantially increased in cortical neurons transfected with HspB1. Co-transfection of HspB1 with specific inhibitors of miR-20a or miR-128 prevented the decrease in PDZ-RhoGEF and blocked the neurite growth promoting effects of HspB1. Using the 3'UTR of PDZ-RhoGEF mRNA in a luciferase reporter construct we observed that HspB1, miR-20a and miR-128 each inhibited luciferase expression. We conclude that HspB1 regulates RhoA activity through modulation of PDZ-RhoGEF levels achieved by translational control through enhanced expression of specific miRNAs (miR-20a and miR-128). Regulation of RhoA activity by translational silencing of PDZ-RhoGEF may be the mechanism through which HspB1 is involved in regulation of neurite growth. As RhoA-GTPase plays a regulatory role in the organization and stability of cytoskeletal networks through its downstream effectors, the results suggest a possible mechanism linking HspB1 mutations and axonal cytoskeletal pathology.
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影响因子：
12.7
作者：
Holmgren A;Bouhy D;De Winter V;Asselbergh B;Timmermans JP;Irobi J;Timmerman V
通讯作者：
Timmerman V
影响因子：
3.3
作者：
Banerjee, J;Wedegaertner, PB
通讯作者：
Wedegaertner, PB
影响因子：
4.8
作者：
Garcia, Melissa C.;Ray, Denise M.;Roberts, John D.
通讯作者：
Roberts, John D.
DOI：
10.1073/pnas.1015691107
发表时间：
2010-11-23
影响因子：
11.1
作者：
Magill, Stephen T.;Cambronne, Xiaolu A.;Goodman, Richard H.
通讯作者：
Goodman, Richard H.
影响因子：
4.2
作者：
Kalmár, B;Burnstock, G;Greensmith, L
通讯作者：
Greensmith, L