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首页> 外文期刊>The Journal of biological chemistry >Identification of MKRN1 as a second E3 ligase for Eag1 potassium channels reveals regulation via differential degradation
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Identification of MKRN1 as a second E3 ligase for Eag1 potassium channels reveals regulation via differential degradation

机译：作为EAG1钾通道的第二E3连接酶的MKRN1鉴定MKRN1揭示了通过差分降解的调节

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Mutations in the human gene encoding the neuron-specific Eag1 voltage-gated K+ channel are associated with neurodevelopmental diseases, indicating an important role of Eag1 during brain development. A disease-causing Eag1 mutation is linked to decreased protein stability that involves enhanced protein degradation by the E3 ubiquitin ligase cullin 7 (CUL7). The general mechanisms governing protein homeostasis of plasma membrane- and endoplasmic reticulum (ER)-localized Eag1 K+ channels, however, remain unclear. By using yeast two-hybrid screening, we identified another E3 ubiquitin ligase, makorin ring finger protein 1 (MKRN1), as a novel binding partner primarily interacting with the carboxyl-terminal region of Eag1. MKRN1 mainly interacts with ER-localized immature core-glycosylated, as well as nascent nonglycosylated, Eag1 proteins. MKRN1 promotes polyubiquitination and ER-associated proteasomal degradation of immature Eag1 proteins. Although both CUL7 and MKRN1 contribute to ER quality control of immature core-glycosylated Eag1 proteins, MKRN1, but not CUL7, associates with and promotes degradation of nascent, nonglycosylated Eag1 proteins at the ER. In direct contrast to the role of CUL7 in regulating both ER and peripheral quality controls of Eag1, MKRN1 is exclusively responsible for the early stage of Eag1 maturation at the ER. We further demonstrated that both CUL7 and MKRN1 contribute to protein quality control of additional disease-causing Eag1 mutants associated with defective protein homeostasis. Our data suggest that the presence of this dual ubiquitination system differentially maintains Eag1 protein homeostasis and may ensure efficient removal of disease-associated misfolded Eag1 mutant channels.
机译：编码神经元特异性EAG1电压门控K +通道的人类基因中的突变与神经发育疾病相关，表明EAG1在脑发育期间的重要作用。引起疾病的EAG1突变与蛋白质稳定性的降低有关，该蛋白质稳定性涉及E3泛素连接酶Cullin 7（Cul7）的增强蛋白质降解。然而，治疗血浆膜和内质网（ER） - 单位化的EAG1K +通道的蛋白质稳态的一般机制仍然不清楚。通过使用酵母双杂交筛选，我们鉴定了另一种E3泛素连接酶的Makorin Ring Finger蛋白1（MKRN1），作为主要与EAG1的羧基末端区域相互作用的新型结合伴侣。 MKRN1主要与ER局部化的未成熟核 - 糖基化相互作用，以及新生的氮胶质化，EAG1蛋白。 MKRN1促进未成熟的EAG1蛋白的多覆和ER相关的蛋白酶体降解。尽管CUL7和MKRN1两者都有助于不成熟的核心糖化的EAG1蛋白的ER质量控制，但MKRN1，但不是CUL7，与ER中新生的NOSCLYCOSYLED EAG1蛋白的降解。与CUL7在调节EAG1的ER和外围质量控制方面的角色直接对比，MKRN1专门负责EAG1成熟的早期阶段。我们进一步证明，CUL7和MKRN1两者都有助于额外疾病的蛋白质质量控​​制，导致与缺陷的蛋白质稳态相关的EAG1突变体。我们的数据表明，这种双泛素化系统的存在差异地保持EAG1蛋白质稳态，可确保有效地去除疾病相关的错误突变频道。

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