RING finger protein 121 facilitates the degradation and membrane localization of voltage-gated sodium channels
RING finger protein 121 facilitates the degradation and membrane localization of voltage-gated sodium channels
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DOI：
10.1073/pnas.1414002112
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发表时间：
2015-03-03
影响因子：
11.1
通讯作者：
Hirata, Hiromi
中科院分区：
文献类型：
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作者：
Ogino, Kazutoyo;Low, Sean E.;Hirata, Hiromi
电压门控钠通道（Na-V）在内质网（ER）中合成后被转运到可兴奋细胞的膜，在那里它们经常聚集，例如在神经元的轴突起始段。虽然钠-钒通道形成和维持簇的机制已被广泛研究，但其运输和降解的过程却很少受到关注。我们进入这些过程的研究开始于分离斑马鱼突变短吻鳄的一个新等位基因，我们发现这是由编码真正有趣的新基因（RING）指蛋白121（RNF 121）的基因突变引起的，RNF 121是一种E3-泛素连接酶，存在于ER和顺式高尔基体区室。在这里，我们证明，RNF 121促进两个相反的命运的Na-V通道：（i）泛素介导的蛋白酶体降解和（ii）膜定位时，与辅助Na-V β亚基共表达。总的来说，这些结果表明，RNF 121参与在其合成和随后的运输到膜的NaV通道的质量控制。
Following their synthesis in the endoplasmic reticulum (ER), voltage-gated sodium channels (Na-V) are transported to the membranes of excitable cells, where they often cluster, such as at the axon initial segment of neurons. Although the mechanisms by which Na-V channels form and maintain clusters have been extensively examined, the processes that govern their transport and degradation have received less attention. Our entry into the study of these processes began with the isolation of a new allele of the zebrafish mutant alligator, which we found to be caused by mutations in the gene encoding really interesting new gene (RING) finger protein 121 (RNF121), an E3-ubiquitin ligase present in the ER and cis-Golgi compartments. Here we demonstrate that RNF121 facilitates two opposing fates of Na-V channels: (i) ubiquitin-mediated proteasome degradation and (ii) membrane localization when coexpressed with auxiliary Na-V beta subunits. Collectively, these results indicate that RNF121 participates in the quality control of NaV channels during their synthesis and subsequent transport to the membrane.