胞质跨膜螺旋通过EMC6驱动的静电相互作用进入内质网膜
Cytosolic transmembrane helices enter the ER membrane through EMC6-driven electrostatic interactions.
摘要(中文译文)
内质网膜蛋白复合物（EMC）促进跨膜结构域（TMD）的插入和小末端结构域的转位。在此，我们确定EMC是上皮钠通道（ENaC）生物合成的关键决定因素。EMC缺失会降低ENaC表达而不影响表面运输，表明其具有生物合成稳定作用。我们证明，ENaC的TMD2带负电的远端段与EMC6上带正电的斑块之间的静电相互作用对于ENaC-EMC结合至关重要。我们提出了一种“半插入酶”机制，其中Sec61转位子部分插入TMD2，使其亲水性远端段暴露于胞质溶胶中。EMC通过静电吸引捕获该段并完成膜整合。生物信息学分析鉴定了一组非经典EMC底物，包括200多种具有类似带电TMD的多跨膜蛋白，表明静电捕获可能是插入非常规亲水性跨膜段的解决方案。此外，我们证明EMC8在稳定EMC方面发挥重要作用——由于其同源物EMC9表达较低且在EMC8缺陷细胞中缺乏代偿性上调，该功能无法被EMC9补偿。这些结果揭示了一种多方面的EMC机制，将插入酶活性与伴侣样稳定作用偶联，以促进含有高度亲水性TMD的多跨膜蛋白的生物合成。
Abstract
The endoplasmic reticulum membrane protein complex (EMC) facilitates transmembrane domain (TMD) insertion and translocation of small terminal domains. Here, we identify EMC as a critical determinant of epithelial sodium channel (ENaC) biosynthesis. EMC loss reduces ENaC expression without affecting surface trafficking, indicating a biosynthetic stabilizing role. We demonstrate that electrostatic interactions between the negatively charged distal segment of ENaC's TMD2 and a positively charged patch on EMC6 are essential for ENaC-EMC association. We propose a 'semi-insertase' mechanism wherein the Sec61 translocon partially inserts TMD2, leaving its hydrophilic distal segment exposed to the cytosol. EMC captures this segment through electrostatic attraction and completes membrane integration. Bioinformatic analysis identified a group of non-canonical EMC clients including >200 multipass proteins with similarly charged TMDs, suggesting that electrostatic capture may represent a solution for inserting unconventional hydrophilic transmembrane segments. Additionally, we demonstrate that EMC8 plays an essential role in stabilizing the EMC-a function that cannot be compensated by its homolog EMC9 due to lower expression and absence of compensatory upregulation in EMC8-deficient cells. These results reveal a multifaceted EMC mechanism coupling insertase activity with chaperone-like stabilization to facilitate biogenesis of multipass membrane proteins containing highly hydrophilic TMDs.
如何引用
AMA
Hongyan Zheng, Wenxue Gu, Tong Zhou, Cecilia M Canessa. Cytosolic transmembrane helices enter the ER membrane through EMC6-driven electrostatic interactions.. Journal of molecular cell biology. 2026; doi:10.1093/jmcb/mjag021.
APA
Hongyan Zheng, Wenxue Gu, Tong Zhou, Cecilia M Canessa (2026). Cytosolic transmembrane helices enter the ER membrane through EMC6-driven electrostatic interactions.. Journal of molecular cell biology. https://doi.org/10.1093/jmcb/mjag021
GB/T 7714
Hongyan Zheng, Wenxue Gu, Tong Zhou, Cecilia M Canessa. Cytosolic transmembrane helices enter the ER membrane through EMC6-driven electrostatic interactions.[J]. Journal of molecular cell biology, 2026 doi:10.1093/jmcb/mjag021.
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